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CN101175481A - Injectable compositions of nanoparticulate immunosuppressive compounds - Google Patents

Injectable compositions of nanoparticulate immunosuppressive compounds Download PDF

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CN101175481A
CN101175481A CNA2006800170788A CN200680017078A CN101175481A CN 101175481 A CN101175481 A CN 101175481A CN A2006800170788 A CNA2006800170788 A CN A2006800170788A CN 200680017078 A CN200680017078 A CN 200680017078A CN 101175481 A CN101175481 A CN 101175481A
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tacrolimus
compositions
sirolimus
dimethyl
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G·利弗西奇
S·詹金斯
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Elan Pharma International Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
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    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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    • A—HUMAN NECESSITIES
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
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    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

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Abstract

The present invention relates to an injectable nanoparticulate immunosuppressant composition for the formation of a subcutaneous or intramuscular depot. The invention is also directed to an injectable composition of nanoparticulate tacrolimus and/or sirolimus which eliminates the need to use polyoxyl 60 hydrogenated castor oil (HCO-60) and/or polysorbate 80 as a solubilizer. This invention further discloses a method of making an injectable nanoparticulate tacrolimus and/or sirolimus composition and is also directed to methods of treatment using the injectable nanoparticulate formulations comprising tacrolimus, sirolimus, or combination thereof for a subcutaneous or intramuscular depot for the prophylaxis of organ rejection and for the treatment of psoriasis or other immune diseases.

Description

The injectable compositions of nanoparticulate immunosuppressive compounds
Technical field
The present invention relates to contain the injectable Nanoparticulate compositions of at least a immunosuppressive compounds.In exemplary embodiment, the invention describes the injectable compositions of nanoparticulate immunosuppressive compounds such as tacrolimus, sirolimus or its combination.
Technical background
The background of A. relevant immunosuppressive compounds
The example of immunosuppressive compounds includes but not limited to tacrolimus and sirolimus.
1. the background of relevant tacrolimus
Tacrolimus, or FK-506 are a kind of macrolide immunosuppressants, it is said it is 100 times that cyclosporin is renderd a service.It is made by a kind of monotype species Su Kuba streptomycete (Streptomyces tsukubaensis) fermentation of streptomycete.United States Patent (USP) 4,894,366 and EPO publication No.0184162 tacrolimus has been described, here be incorporated by reference in this text and examine.
Tacrolimus is with PROGRAF (can be by Fujisawa USA, Inc. obtain) trade name sell, it suppresses some humoral immunization, and suppressing cell-mediated reaction to a greater extent, for example repulsion of allograft, delayed hypersensitivity, collagen-induced arthritis, experimental allergic encephalomyelitis and graft versus host disease.Tacrolimus has prolonged the survival period of host and graft in the zoografting model of liver, kidney, heart, bone marrow, small intestinal and pancreas, lung and trachea, skin, cornea and extremity.
Experimental evidence shows that tacrolimus combines with intracellular protein FKBP-12.Form the complex of tacrolimus-FKBP-12, calcium, calmodulin, CaM and calcinerin then, the phosphatase activity of calcinerin is suppressed.This effect can prevent the dephosphorylation and the transposition of activating T cell nuclear factor (NF-AT), and NF-AT is considered to cause to form a kind of nuclear consitution of the required genetic transcription of lymphokine (for example interleukin-2, gamma interferon).Its overall result is to suppress the lymphocytic activation of T-(that is immunosuppressive action).
The empirical formula C of tacrolimus 44H 69NO 12H 2O, molecular weight are 822.05.Tacrolimus is white crystal or crystalline powder, and is water-soluble hardly, easily dissolving in ethanol, very easily dissolving in methanol and chloroform.The chemical constitution of tacrolimus is as follows:
(referring to The Merck Index, the 12nd edition, 9200, Merck﹠amp; Co., Inc., Rahway, NJ, 1996).
Tacrolimus is not exclusively with Protean in the absorption of oral back in gastrointestinal tract.The absolute bioavailability of tacrolimus in the renal transplant recipients (N=26) of growing up is 17 ± 10%, is 22 ± 6% in adult liver-transplantation patients (N=17), is 18 ± 5% (N=16) in the volunteer of health.
The single dose that carries out in the volunteer of 32 health has been determined 1mg and the capsular bioequivalence of 5mg.Another single dose that carries out in 32 healthy volunteers has been determined 0.5mg and the capsular bioequivalence of 1mg.Maximum haemoconcentration (the C of tacrolimus Max) and area under curve (AUC) in the healthy volunteer of 18 fasting accepting 3mg, 7mg and 10mg single oral dose, similarly be to increase in the mode that is proportional to dosage.
In 18 renal transplant recipients, the tacrolimus paddy concentration 3-30mg/mL (C that after taking medicine 10-12 hour, records Min) with the dependency fine (correlation coefficient 0.93) of AUC.In concentration range is that correlation coefficient is 0.94 in 24 liver-transplantation patients of 10-60mg/mL.
About the influence of food, the infiltration rate of tacrolimus and degree are maximum under fasted conditions.When 15 healthy volunteers were used, the existence of food and composition had reduced the infiltration rate and the degree of tacrolimus.This influence of high lipid diet (848 kilocalories, 46% fat) is the most remarkable: average A UC and C MaxReduce by 37% and 77% respectively, T Max5 times have been prolonged.High carbohydrate diet (668 kilocalories, 85% carbohydrate) is with average A UC and average C MaxReduce by 28% and 65% respectively.
In the volunteer of health (N=16), the meal time also influences the bioavailability of tacrolimus.When using immediately after the meal, compare average C with fasted conditions MaxDescend 71%, average A UC descends 39%.When after having meal 1.5 hours, using, compare average C with fasted conditions MaxDescend 63%, average A UC descends 39%.
In 11 liver-transplantation patients, use tacrolimus at high fat (400 kilocalories, 34% fat) breakfast after 15 minutes, compare with fasted conditions, cause AUC (27 ± 18%) and C Max(50 ± 19%) reduce.
The plasma protein combination of tacrolimus is about 99%, and irrelevant with concentration in the scope of 5-50ng/ml.Tacrolimus mainly combines with albumin and α-1-acidoglycoprotein, and associate with the erythrocyte height.Several Factors is depended in the distribution of tacrolimus between whole blood and blood plasma, for example temperature, drug level and the plasma protein concentration when hematocrit, separating plasma.In a research of the U.S., the ratio average out to 35 (scope is 12-67) of whole blood concentration and plasma concentration.
Tacrolimus by mixed function oxidase system, mainly be that cytochrome P-450 system (CYP3A) carries out metabolism widely.Proposed to cause forming the metabolic pathway of 8 kinds of possible metabolites.Demethylation and hydroxylation are called as the main mechanism that external biological transforms.The main metabolite of being discerned in people's hepatomicrosome is cultivated is a 13-demethylation tacrolimus.In in vitro tests, reported 31-demethylation metabolite and had the activity identical with tacrolimus.
In healthy volunteer, the renal transplant recipients of growing up and adult liver-transplantation patients, the average clearance rate after the intravenous of tacrolimus is used is respectively 0.040,0.083 and 0.053L/hr/kg.In human body, the dosage of being used less than 1% is drained in urine steadily.
In the mass balance research of the radiolabeled tacrolimus of using to 6 healthy volunteers' intravenous, radiolabeled average recovery rate is 77.8 ± 12.7%.Feces is discharged and to be accounted for 92.4 ± 1.0%, based on radioactive discharge half-life be 48.1 ± 15.9 hours, and based on tacrolimus concentration, it is 43.5 ± 11.6 hours.Radiolabeled average clearance rate is 0.029 ± 0.015L/hr/kg, and the clearance rate of tacrolimus is 0.029 ± 0.009L/hr/kg.When oral using, radiolabeled average recovery rate is 94.9 ± 30.7%.Feces is discharged and to be accounted for 92.6 ± 30.7%, and urine is discharged and accounted for 2.3 ± 1.1%, based on radioactive discharge half-life be 31.9 ± 10.5 hours, and based on tacrolimus concentration, it is 48.4 ± 12.3 hours.Radiolabeled average clearance rate is 0.226 ± 0.116L/hr/kg, and the clearance rate of tacrolimus is 0.172 ± 0.088L/hr/kg.
To can not oral PROGRAF Capsular patient can use PROGRAF The injection begin treatment.When considering to use PROGRAF During injection, should be noted that with containing castor oil derivative such as CREMAPHOR The tacrolimus injection thing anaphylaxis once took place.Therefore, HCO-60 (polyoxyethylene (60) castor oil hydrogenated) patient hypersensitive is forbidden PROGRAF Injection.PROGRAF Initial dose should use back 6 hours of transplanting at once.The PROGRAF of suggestion The predose of injection is 0.03-0.05mg/kg/ days, continuously intravenous infusion.Adult patients should be with the lower limit acceptable dose of dosage range.The adrenocortical steroid treatment is carried out in early stage suggestion simultaneously after transplanting.PROGRAF Continuous intravenous (IV) infusion of injection should only last till that the patient can tolerate oral PROGRAF Till the capsule.
Before the use, PROGRAF Injection must be 0.004-0.02mg/mL until concentration with 0.9% sodium chloride injection or the dilution of 5% glucose injection.The transfusion of dilution should be stored in glass or the polyethylene can, and should abandon after 24 hours.The transfusion of dilution should not be stored in the PVC container, because stability can reduce, and the probability that has phthalate (ester) to come together and.In the situation of using rarer solution (for example department of pediatrics make up a prescription etc.), should use the pipe of PVC-free equally, be adsorbed on probability on the pipe to minimize high amount of drug.Whenever solution and container permission, the outer drug products of intestinal should visual inspection particulate matter and variable color situation before using.Because PROGRAF Chemical instability in alkaline medium, PROGRAF Injection should be not 9 or higher solution (for example ganciclovir or acyclovir) mixes or infusion altogether with pH.
If intravenous therapy is essential, suggestion converts oral tacrolimus to from intravenous immediately in the time can tolerating oral medication.In accepting the patient of intravenous infusion, oral medication dosage should carry out after stopping intravenous infusion 8-12 hour first.The initial oral dose of tacrolimus capsule of suggestion is 0.10-0.15mg/kg/ days, uses by two fens daily doses with per 12 hours.Reported that common clothes grapefruit juice improves the tacrolimus blood paddy concentration of liver-transplantation patients.Make up a prescription and to determine according to the clinical assessment of repulsion and toleration.
2. about the background of sirolimus
Sirolimus is the inhibitive ability of immunity macrolide that is generated by moisture absorption streptomycete (Streptomyces hygroscopicus).The chemical name of sirolimus (also claiming rapamycin) is (3S, 6R, 7E, 9R, 10R, 12R, 14S, 15E, 17E, 19E, 21S, 23S, 26R, 27R, 34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-16 hydrogen-9, the 27-dihydroxy-3-[(1R)-2-[(1S, 3R, 4R)-4-hydroxyl-3-methoxyl group cyclohexyl]-the 1-Methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido [2,1-c] [1,4] oxa-azepine hentriacontine-1,5,11,28,29 (4H, 6H, 31H)-five ketone.Its molecular formula is C 51H 79NO 13, molecular weight is 914.2.The structural formula of sirolimus is as follows.
Figure S2006800170788D00051
Sirolimus is white to pale powder, water insoluble, but is soluble in benzylalcohol, chloroform, acetone and acetonitrile.Sirolimus is that form with peroral dosage form is with trade name Rapamune at present (Madison N.J.) sells by Wyeth-Ayerst Inc..Rapamune Form with the oral liquid that contains the 1mg/mL sirolimus is used.Rapamune is in addition with white, triangle tablet that contains the 1-mg sirolimus and the extremely form acquisition of cream-coloured triangle tablet of yellow that contains the 2-mg sirolimus.
Rapamune Non-active ingredient in the oral liquid is Phosal50 PG (phosphatidylcholine, propylene glycol, list and two-glyceride, ethanol, soya bean fatty acid and ascorbyl palmitate) and polyoxyethylene sorbitan monoleate.The Rapamune oral liquid comprises 1.5%-2.5% ethanol.Rapamune Non-active ingredient in the tablet comprises sucrose, lactose, Polyethylene Glycol 8000, calcium sulfate, microcrystalline Cellulose, medicine glaze (pharmaceutical glaze), Talcum, titanium dioxide, magnesium stearate, polyvidone, poloxamer 188, Polyethylene Glycol 20,000, glycerin mono-fatty acid ester, Brazil wax and other compositions.2 milligrams of dosage forms also comprise iron oxide yellow 10 and iron oxide brown 70.
Sirolimus suppresses T-lymphocyte activation and propagation (it is response is stimulated and taken place by antigen that the mechanism that is different from other immunosuppressant caused and cytokine (interleukin [IL]-2, IL-4 and IL-15)).Sirolimus also suppresses antibody and produces.In cell, but being attached to, sirolimus exempts from albumen, conjugated protein-12 (FKBP-12) of FK are to produce immunosuppressive compound.Sirolimus: the FKBP-12 complex is to the active not influence of calcinerin.This complex in conjunction with and suppress mammalian target (mTOR)---a kind of kinase whose activation of adjusting of key of sirolimus.The propagation of the T cell of cytokine driving has been suppressed in this inhibition, has suppressed cell cycle from G 1Process to the S phase.
Studies show that in experimental model, in mice, rat, pig and/or primate, sirolimus makes the survival of allograft's (kidney, heart, skin, islets of langerhans, small intestinal, pancreas duodenum and bone marrow) obtain prolongation.In rat, sirolimus has reversed the acute rejection of the allograft of heart and kidney, and makes the survival of graft obtain prolongation in the rat of pre-sensitizing.In some researchs, after ending treatment, the immunosuppressive action of sirolimus has continued to reach 6 months.This toleration effect is that alloantigen is specific.
In the rodent model of autoimmune disease, it is relevant to autoimmune tunica uvea retinitis with systemic lupus erythematosus (sle), collagen-induced arthritis, autoimmune type i diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft versus host disease immune-mediated incident that sirolimus has suppressed.
In health volunteer, the saturating dialysis patient of department of pediatrics, hepatic injury patient and renal transplant recipients, after oral, determined sirolimus pharmacokinetics activity.Using Rapamune After the oral liquid, sirolimus is by fast Absorption, in the health volunteer behind single dose, to (T average time of Cmax Max) be approximately 1 hour, and in renal transplantation person, after giving many oral doses, be approximately 2 hours to average time of Cmax.Using Rapamune After the oral liquid, estimate that the system availability of sirolimus is about 14%.After using tablet, the average bioavailability of sirolimus is higher than oral liquid for being approximately 27%.Sirolimus oral tablet and oral liquid are not bioequivalent; Yet, under the 2mg dosage level, verified clinical equivalent.With Rapamune After oral liquid was applied to stable renal transplant recipients, sirolimus concentration and dosage were proportional, at 3-12mg/m 2
B. about the background of nano-particle surfactant composition
The nano-particle surfactant composition sees United States Patent (USP) 5,145 the earliest, and 684 (' 684 patents) comprise the poorly soluble treatment or the granule of diagnostic agent, and absorption or associating noncrosslinking surface stabilizer are arranged in its surface.' 684 patents have also been described the method for preparing this nano-particle surfactant composition, but do not mention the compositions of the tacrolimus that contains form of nanoparticles.At the United States Patent (USP) 5 that is entitled as " Method of Grinding Pharmaceutical Substances ", 518,187 and 5,862,999, the United States Patent (USP) 5 that is entitled as " Continuous Method of Grinding PharmaceuticalSubstances ", 718,388, with the United States Patent (USP) 5 that is entitled as " Process of PreparingTherapeutic Compositions Containing Nanoparticles ", in 510,118, the method for making Nanoparticulate compositions has been described.
In addition, U.S. Patent application 20020012675A1 (announced on January 31st, 2002: ontrolled Release Nanoparticulate Compositions) described Nanoparticulate compositions, and be incorporated into this paper especially as a reference.These reference papers are not all described the compositions of Nanoparticulate tacrolimus or nano-particle sirolimus.
US 20030054042 (Stabilization of chemical compounds usingnanoparticulate formulations) has described nano-particle rapamycin preparation, and it comprises injectable preparation.United States Patent (USP) 5,989,591 (Rapamycin formulations for oraladministration) have described the oral nano-particle rapamycin composition that is used for of Tabules.
Amorphous granule compositions has for example been described: United States Patent (USP) 4,783,484:Particulate Composition and Use Thereof as Antimicrobial Agent in following patent; United States Patent (USP) 4,826,689:Method for Making Uniformly Sized Particles from Water-Insoluble Organic Compounds; United States Patent (USP) 4,997,454:Method for MakingUniformly-Sized Particles From Insoluble Compounds; United States Patent (USP) 5,741,522:Ultrasmall, Non-aggregated Porous Particles of Uniform Size for EntrappingGas Bubbles Within and Methods; With United States Patent (USP) 5,776,496:UltrasmallPorous Particles for Enhancing Ultrasound Back Scatter; It all is incorporated into this paper as a reference especially.
The compositions that needs immunosuppressant such as tacrolimus and sirolimus, it has enhanced dissolution characteristics, and it when being applied to the patient, provides enhanced bioavailability again, and the feed that reduces/fasting absorbs variability.By the method and composition of the injectable nanoparticle formulations that comprises tacrolimus, sirolimus or its combination is provided, the present invention has satisfied these needs.This injectable nanoparticle formulations has been eliminated using the needs of solubilizing agent such as polyoxyethylene (60) castor oil hydrogenated (HCO-60) or Polysorbate such as polyoxyethylene sorbitan monoleate.
Summary of the invention
The present invention relates to a kind of injectable nanoparticle formulations, it comprises immunosuppressive compounds such as tacrolimus, sirolimus or its combination.This nanoparticle formulations makes and can discharge continuously from the injection site with the speed of expectation by the granularity that changes tacrolimus, sirolimus or its combination.In one embodiment, described preparation is a kind of injectable compositions, and it can be used in subcutaneous or intramuscular injection, provides medicine the long-term storage point (depot) that discharges thereby formed.This preparation has been guaranteed pharmacology's effect and patient's compliance preferably.
The present invention also provides a kind of injectable immunosuppressant preparation, and it comprises Nanoparticulate tacrolimus, nano-particle sirolimus or its combination, and wherein effective particle mean size of tacrolimus and/or sirolimus is less than about 2000nm.In addition, described compositions comprises at least a surface stabilizer, its absorption or associate in tacrolimus and/or the particulate surface of sirolimus.In other embodiments of the present invention, the particulate effective particle mean size of Nanoparticulate tacrolimus or sirolimus is less than about 1900nm, less than about 1800nm, less than about 1700nm, less than about 1600nm, less than about 1500nm, less than about 1400nm, less than about 1300nm, less than about 1200nm, less than about 1250nm, less than about 1000nm, less than about 900nm, less than about 800nm, less than about 700nm, less than about 600nm, less than about 550nm, less than about 500nm, less than about 450nm, less than about 400nm, less than about 350nm, less than about 300nm, less than about 250nm, less than about 200nm, less than about 150nm, less than about 100nm, less than about 7nm, or less than about 50nm.
Another aspect of the present invention provides the preparation of injectable Nanoparticulate tacrolimus, nano-particle sirolimus or tacrolimus/sirolimus combination, and it has eliminated use polyoxyethylene (60) castor oil hydrogenated (HCO-60) and/or the polyoxyethylene sorbitan monoleate needs as solubilizing agent.This is useful, because conventional injectable tacrolimus of non-nano granule or sirolimus preparation comprise that polyoxyethylene (60) castor oil hydrogenated or polyoxyethylene sorbitan monoleate are as solubilizing agent.The existence of this solubilizing agent may cause patient's anaphylactic shock (being serious allergy) and death.
The present invention also provides the preparation of the tacrolimus, sirolimus or its combination that contain high concentration in volume injected, has formed to have storage point slow, long-term medicine dissolution when using.
In another aspect of this invention, provide a kind of preparation to contain the method for the injectable nano-particle immunosuppressant preparation of tacrolimus, sirolimus or its combination.Described method comprises: (1) disperses selected immunosuppressive compounds in liquid dispersion medium; (2) with mechanical means the particle size reduction of immunosuppressive compounds is arrived effective particle mean size of expectation, for example less than about 2000nm.Before the particle size reduction of immunosuppressive compounds, among or afterwards, one or more surface stabilizers can be added in the compositions.In one embodiment, described surface stabilizer is that molecular weight is less than about 40,000 daltonian polyvidone polymer.Preferably, in the particle size reduction process, liquid dispersion medium is maintained the physiological pH level, for example about 3-about 8.
The invention still further relates to and use the of the present invention injectable nanoparticle formulations treatment that contains tacrolimus, sirolimus or its combination to comprise the method for people's mammal with the prevention organ rejection.For example, described compositions is useful for the patient who accepts allogeneic liver or renal transplantation and treatment psoriasis or other immune disease.Said method comprising the steps of: the injectable nanoparticle formulations that will treat tacrolimus, sirolimus or its combination of effective dose is applied to the experimenter through subcutaneous or intramuscular injection, makes to form the storage point therein so that the chronic administration of medicine.
Injectable Nanoparticulate tacrolimus of the present invention or sirolimus preparation can randomly comprise the acceptable excipient of one or more pharmacologys, as the acceptable liquid-carrier of avirulent physiology, pH regulator agent or antiseptic.
More than general introduction and following detailed description all are exemplary with illustrative, all are intended to provide the further explanation to as the present invention for required protection.By following detailed description of the invention, other purpose, advantage and novel feature will be conspicuous to those skilled in the art.
Description of drawings
Fig. 1. the 100X light micrograph taken of the employing phase place optical technology of the tacrolimus of Yan Moing not.
Fig. 2. have the 100X light micrograph that the employing phase place optical technology of 10% (w/w) Nanoparticulate tacrolimus (Camida LLC) aqueous dispersion of 2% (w/w) polyvinylpyrrolidone (PVP) K29/32 and 0.05% (w/w) dioctylsulfosuccinat (DOSS) is taken.
Fig. 3. have the 100X light micrograph of the employing phase place optical technology shooting of 10% (w/w) Nanoparticulate tacrolimus (Camida LLC) aqueous dispersion after a week is stored in cold preservation of 2% (w/w) polyvinylpyrrolidone (PVP) K29/32 and 0.05% (w/w) dioctylsulfosuccinat (DOSS).
Fig. 4. have the 100X light micrograph that the employing phase place optical technology of 10% (w/w) Nanoparticulate tacrolimus (Camida LLC) aqueous dispersion of 2% (w/w) PVP K12 and 0.15% (w/w) NaTDC is taken.
Fig. 5. have 3% (w/w) Plasdone The 100X light micrograph that the employing phase place optical technology of 20% (w/w) Nanoparticulate tacrolimus (CamidaLLC) aqueous dispersion of S630 (ratio of vinyl pyrrolidone and vinyl acetate is 60: 40 a random copolymer) is taken.
Fig. 6. have 3% (w/w) Plasdone The 100X light micrograph that the employing phase place optical technology of 20% (w/w) Nanoparticulate tacrolimus (CamidaLLC) aqueous dispersion of S630 (ratio of vinyl pyrrolidone and vinyl acetate is 60: 40 a random copolymer) after a week is stored in cold preservation taken.
Fig. 7. have the 100X light micrograph that the employing phase place optical technology of 10% (w/w) Nanoparticulate tacrolimus (Camida LLC) aqueous dispersion of 2% (w/w) hydroxypropyl cellulose (HPC-SL) and 0.1% (w/w) DOSS is taken.
Fig. 8. have the 100X light micrograph that the employing phase place optical technology of 5% (w/w) Nanoparticulate tacrolimus (Camida LLC) aqueous dispersion of 1% (w/w) HPC-SL and 0.15% (w/w) DOSS is taken.
Fig. 9. have the 100X light micrograph of the employing phase place optical technology shooting of 5% (w/w) Nanoparticulate tacrolimus (Camida LLC) aqueous dispersion after cold preservation is stored 12 days of 1% (w/w) HPC-SL and 0.15% (w/w) DOSS.
Figure 10. have the 100X light micrograph that the employing phase place optical technology of 5% (w/w) Nanoparticulate tacrolimus (Camida LLC) aqueous dispersion of 1% (w/w) HPC-SL and 0.1% (w/w) NaTDC is taken.
Figure 11. have the 100X light micrograph of the employing phase place optical technology shooting of 5% (w/w) Nanoparticulate tacrolimus (Camida LLC) aqueous dispersion after cold preservation is stored 12 days of 1% (w/w) HPC-SL and 0.1% (w/w) NaTDC.
Figure 12. have the 100X light micrograph that the employing phase place optical technology of rice granule tacrolimus (Camida LLC) aqueous dispersion in 10% (w/w) of 2% (w/w) hydroxypropyl emthylcellulose (HPMC) and 0.05% (w/w) DOSS is taken.
Figure 13. have the 100X light micrograph of the employing phase place optical technology shooting of 10% (w/w) Nanoparticulate tacrolimus (Camida LLC) aqueous dispersion after a week is stored in cold preservation of 2% (w/w) hydroxypropyl emthylcellulose (HPMC) and 0.05% (w/w) DOSS.
Figure 14. have 2%Pluronic The 100X light micrograph that the employing phase place optical technology of 10% (w/w) Nanoparticulate tacrolimus (Camida LLC) aqueous dispersion of F108 is taken.
Figure 15. have 2%Pluronic The 100X light micrograph that the employing phase place optical technology of 10% (w/w) Nanoparticulate tacrolimus (Camida LLC) aqueous dispersion of F108 after a week is stored in cold preservation taken.
Figure 16. have 2%Tween The 100X light micrograph that the employing phase place optical technology of 80 10% (w/w) Nanoparticulate tacrolimus (CamidaLLC) aqueous dispersion is taken.
Figure 17. have 2%Tween The 100X light micrograph that the employing phase place optical technology of 80 10% (w/w) Nanoparticulate tacrolimus (CamidaLLC) aqueous dispersion after a week is stored in cold preservation taken.
Detailed description of the invention
A. foreword
The present invention relates to comprise the composition of the injectable formulation of injectable nano particle immunosupress preparation such as Nanoparticulate tacrolimus, nano particle sirolimus or its combination. Used immunodepressant can be the immunodepressant of any poorly water-soluble among the present invention. In one embodiment of the present invention, immunodepressant is tacrolimus, sirolimus or its combination. Effective particle mean size of nano particle immunodepressant is less than about 2000nm.
Compare with tacrolimus or sirolimus routine, non-nano particle or dissolved form, contain Nanoparticulate tacrolimus, nano particle sirolimus or its combination preparation of the present invention advantage including, but not limited to: it is water-soluble that (1) increases; (2) bioavailability that increases; (3) because the less formulation size that the bioavailability that strengthens causes; (4) because the lower therapeutic dose that the bioavailability that strengthens causes; (5) because the risk of the reduction of undesirable side effect that lower dosage causes; (6) the patient's convenience and the compliance that strengthen; (7) more effective prevention organ rejection or more effective treatment psoriasis or other immunity disease behind the organ valve replacement. Than the conventionally form of injectable tacrolimus or sirolimus, the further advantage that contains the injectable nanoparticle formulations of tacrolimus, sirolimus or its combination of the present invention is to have eliminated use polyoxyethylene (60) rilanit special (HCO-60) or polysorbate such as polyoxyethylene sorbitan monoleate as the needs of solubilizer.
The present invention also comprises the Nanoparticulate compositions that contains tacrolimus, sirolimus or its combination and one or more nontoxic physiology acceptable carriers, auxiliary agent or mediator (being generically and collectively referred to as carrier). These compositions can be mixed with for enteron aisle and (for example inject outward, intravenous, muscle or subcutaneous), oral with solid, liquid or aerosol form, vagina, nose, rectum, eye, part (powder, ointment or drops), contain in clothes, the brain pond, in the peritonaeum or surface applied etc.
B. definition
Described in following and entire chapter application, with some definition the present invention is described herein.
Term used herein " less than effective particle mean size of about 2000nm " mean when with for example sedimentation field flow fractionation, Photon Correlation Spectrum, light scattering, disc type is centrifugal and other technology well known by persons skilled in the art when measuring, the size of at least 50% tacrolimus, sirolimus or tacrolimus and sirolimus particle is less than about 2000nm by weight.
As used in this article, " pact " should be understood by those of ordinary skills, and variation to a certain degree will be arranged with the context of its used part. If according to the context of term application, to those skilled in the art, its use is not clearly, and " pact " meaning is to be no more than positive and negative 10% of described particular term so.
As used herein, about stable tacrolimus or sirolimus granule, term " stable " is including but not limited to one or more following parameters: (1) along with the past of time, and tacrolimus or sirolimus granule do not have because the mutual gravitation of granule and significantly flocculation or cohesion or granularity obviously increase; (2) along with the past of time, the particulate physical arrangement of tacrolimus or sirolimus can not change, and for example changes crystalline phase into from amorphous phase; (3) tacrolimus or sirolimus granule are chemically stable; And/or (4) the preparation nano-particle process of the present invention in, at the fusing point of tacrolimus or sirolimus or more than the fusing point, tacrolimus and/or sirolimus do not experience heating steps.
Term " routine " or " non-nano granule " tacrolimus, sirolimus or its combination should refer to the activating agent of dissolved or effective particle mean size greater than about 2000nm.Effective particle mean size of nano-particle activating agent as defined herein is less than about 2000nm.
Phrase " medicine of poorly water-soluble " as used in this article is meant in the water dissolubility less than about 30mg/mL, less than about 20mg/mL, and less than about 10mg/mL, or less than the medicine of about 1mg/mL.
As used herein, the drug dose that provides specific pharmacology to respond for the medicine of being used in numerous experimenters of the described treatment of needs should be provided phrase " treatment effective dose ".Should emphasize that under particular condition, the medicine of the treatment effective dose that particular subject is used even described dosage is thought to treat effective dose by those skilled in the art, will be always ineffective aspect the described symptom/disease of treatment herein.
As used in this article, term " granule " is meant the state of matter that exists for feature with discrete particle, pill, beadlet or granule, and no matter its size, shape or form how.As used in this article, term " many granules " is meant a plurality of discrete or accumulative granule, pill, beadlet, granule or its mixture, and regardless of its size, shape or form how.
C. the feature of nano-particle immunosuppressant composite
Nano-particle immunosuppressant composite of the present invention has a lot of enhanced pharmacological characteristics.
1. the bioavailability of Zeng Jiaing
Compare with existing conventional tacrolimus or sirolimus preparation, the preparation that contains tacrolimus, sirolimus or its combination of the present invention shows the bioavailability of increase under the same dosage of identical tacrolimus, sirolimus or its combination.
Abiotic equivalence is important, demonstrates obviously bigger drug absorption because this means the nano-particle dosage form of tacrolimus, sirolimus or its combination.For with the bioequivalent nano-particle dosage form of conventional crystallite dosage form, this nano-particle dosage form will necessarily comprise significantly less medicine.Thereby the nano-particle dosage form has increased the bioavailability of medicine significantly.
And the nano-particle dosage form that contains tacrolimus, sirolimus or its combination requires still less medicine to obtain and conventional crystallite dosage form (PROGRAF for example ) viewed identical pharmacotoxicological effect.Therefore, than the crystallite dosage form of routine, the nano-particle dosage form has the bioavailability of increase.
2. the pharmacokinetic characteristic of tacrolimus of the present invention and/or sirolimus compositions is not taken in experimenter's the feed of said composition or the influence of fasting state
The present composition comprises tacrolimus, sirolimus or its combination, and wherein the pharmacokinetic characteristic of tacrolimus, sirolimus or its combination is not taken in experimenter's the feed of said composition or the influence of fasting state basically.This means that with respect to fasting, when using the Nanoparticulate compositions that contains tacrolimus, sirolimus or its combination under the state on the feed, drug absorption or drug absorption speed almost do not have or do not have tangible difference.
Basically the benefit of eliminating the dosage form of food effect comprises: increased experimenter's convenience, thereby improved experimenter's compliance, because described experimenter does not need to guarantee that they are having food or are not having under the condition of food and take medicine.This is important, because under experimenter's compliance condition relatively poor to tacrolimus or sirolimus, may observe the enhancing of the medical symptom that this medicine is used for treating, for example the patient may suffer the organ rejection, perhaps psoriasis or other immune diseases is not treated.
The present invention also preferably provides the compositions that contains tacrolimus, sirolimus or its combination, and it has desirable pharmacokinetic characteristic when being applied to mammalian subject.The desirable pharmacokinetic characteristic that contains the compositions of tacrolimus, sirolimus or its combination preferably includes but is not limited to: (1) is when analyzing the blood plasma of the mammalian subject after using, use the C of tacrolimus, sirolimus or its combination with same dose MaxBe preferably more than the C of non-nano granule tacrolimus or sirolimus preparation MaxAnd/or (2) use with same dose when the blood plasma of the mammalian subject after using is analyzed, and the AUC of tacrolimus, sirolimus or its combination is preferably more than the AUC of non-nano granule tacrolimus or sirolimus preparation; And/or (3) use the T of tacrolimus, sirolimus or its combination with same dose when the blood plasma of the mammalian subject after using is analyzed MaxPreferably less than the T of non-nano granule tacrolimus or sirolimus preparation MaxAs used in this article, desirable pharmacokinetic characteristic is a pharmacokinetic characteristic measured behind the initial dose of tacrolimus, sirolimus or its combination.
In one embodiment, use with same dose, with the comparative drug dynamic test of non-nano granule tacrolimus or sirolimus preparation in, the compositions display that contains tacrolimus, sirolimus or its combination goes out T MaxBe not more than non-nano granule tacrolimus or the shown T of sirolimus preparation MaxAbout 90%, about 80%, about 70%, about 60%, about 50%, about 30%, about 25%, about 20%, about 15%, about 10% or about 5%.
In another embodiment, with the comparative drug dynamic test of non-nano granule tacrolimus or sirolimus preparation in, use with same dose, the compositions display that contains tacrolimus, sirolimus or its combination of the present invention goes out C MaxGreater than the shown C that goes out of non-nano granule tacrolimus or sirolimus preparation MaxAt least about 50%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%, at least about 1100%, at least about 1200%, at least about 1300%, at least about 1400%, at least about 1500%, at least about 1600%, at least about 1700%, at least about 1800% or at least about 1900%.
In another embodiment, with the comparative drug dynamic test of non-nano granule tacrolimus or sirolimus preparation in, use the tacrolimus that contains of the present invention with same dose, the compositions display of sirolimus or its combination go out AUC greater than the shown AUC that goes out of non-nano granule tacrolimus or sirolimus preparation at least about 25%, at least about 50%, at least about 75%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, at least about 750%, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, at least about 1000%, at least about 1050%, at least about 1100%, at least about 1150% or at least about 1200%.
3. with respect to fasting state, the bioequivalence that contains the compositions of immunosuppressive compounds of the present invention when using under the state on the feed
The present invention also comprises the compositions that contains Nanoparticulate tacrolimus, nano-particle sirolimus or its combination, wherein under fasting state the experimenter is used the said composition bioequivalence under the state experimenter being used said composition on the feed.With respect to fasting state, when using under the state on the feed, contain Nanoparticulate tacrolimus, nano-particle sirolimus or its combination compositions absorption difference preferably less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5% or less than about 3%.
In one embodiment of the invention, the present invention includes the compositions that contains Nanoparticulate tacrolimus, nano-particle sirolimus or its combination, wherein under fasting state, the experimenter is used the said composition bioequivalence under the state experimenter being used said composition on the feed, particularly as by FDA and the given C of corresponding European administrative organization (EMEA) MaxDefined with the AUC guide.According to the U.S. FDA guide, if AUC and C Max90% confidence interval (CI) be in 0.80 to 1.25 between (with regard to regulating purpose, T MaxMeasure uncorrelated with bioequivalence), then two kinds of products or method are bioequivalent.According to European EMEA guide, in order to demonstrate two kinds of chemical compounds or to use bioequivalence between the situation, 90% the CI of AUC must be between 0.80 to 1.25, and C Max90% CI must be between 0.70 to 1.43.
4. the solubility curve of immunosuppressant composite of the present invention
The compositions that contains tacrolimus, sirolimus or its combination of the present invention has wonderful solubility curve unexpectedly.The quick dissolving of the activating agent of being used is preferred, because dissolving generally can cause having an effect quickly and bigger bioavailability faster.In order to improve solubility curve and the bioavailability that contains tacrolimus, sirolimus or its combination, it is useful that the dissolving of raising medicine makes its level that can reach near 100%.
The compositions that contains tacrolimus, sirolimus or its combination of the present invention preferably has such solubility curve, and is wherein dissolved at least about 20% compositions in about 5 minutes.In other embodiments of the present invention, at least about 30% or in about 5 minutes, dissolve at least about 40% the compositions that contains tacrolimus, sirolimus or its combination.In other embodiments of the present invention, preferably at least about 40%, at least about 50%, at least about 60%, at least about 70% or in about 10 minutes, dissolve at least about 80% the compositions that contains tacrolimus, sirolimus or its combination.At last, in another embodiment of the present invention, preferably at least about 70%, at least about 80%, at least about 90% or in about 20 minutes, dissolve at least about 100% the compositions that contains tacrolimus, sirolimus or its combination.
Dissolving is preferably measured in the identification medium.A kind of like this dissolve medium will produce two kinds of solubility curves very inequality to two kinds of products that have very different solubility curves in gastric juice, that is, and and dissolving situation in the body of this dissolve medium prediction group compound.Exemplary dissolve medium is the aqueous medium that contains 0.025M surfactant sodium lauryl sulphate.Can pass through the dissolved amount of spectrophotometry.Turn blade method (European Pharmacopoeia) can be used to measure the dissolving situation.
5. the stability of immunosuppressant composite in biological associated media
The other characteristics that contain the compositions of tacrolimus, sirolimus or its combination of the present invention are to work as to be dispersed in the biological associated media, and described compositions keeps nano particles basically.Existing situation in the biological associated media parody.Because nano-particle surfactant composition of the present invention is benefited from the small grain size of activating agent; If when using, activating agent does not keep nano particles basically, the active agent particle that can form " agglomerate " so or reunite.Along with the formation of this agglomerated particle, the bioavailability of dosage form may reduce.
Preferably, after disperseing in biological associated media, compositions of the present invention keeps the effective particle mean size less than about 2000nm.In other embodiments of the present invention, the particulate effective particle mean size of the tacrolimus of redispersion of the present invention and/or sirolimus is less than about 1900nm, less than about 1800nm, less than about 1700nm, less than about 1600nm, less than about 1500nm, less than about 1400nm, less than about 1300nm, less than about 1200nm, less than about 1100nm, less than about 1000nm, less than about 900nm, less than about 800nm, less than about 700nm, less than about 650nm, less than about 600nm, less than about 550nm, less than about 500nm, less than about 450nm, less than about 400nm, less than about 350nm, less than about 300nm, less than about 250nm, less than about 200nm, less than about 150nm, less than about 100nm,, as pass through light scattering method less than about 75nm or less than about 50nm, microtechnique or other appropriate method are measured.The described method that is suitable for measuring effective particle mean size is for known to those of ordinary skills.
The aqueous medium that this biology is relevant can be any aqueous medium that demonstrates desired ionic strength and pH, and described ionic strength and pH have constituted the basis of the biological dependency of medium.Desired pH and ionic strength are the representatives of the physiological conditions that exists in human body.The aqueous medium that this biology is relevant can be aqueous solution or its combination that for example demonstrates electrolyte aqueous solution or any salt, acid or the alkali of desired pH value and ionic strength.
Biological relevant pH is well-known in the art.For example, under one's belt, the pH scope is from being slightly less than 2 (but generally greater than 1) until 4 or 5.In small intestinal, pH can be 4-6.In colon, it can be 6-8.Biological relevant ionic strength also is well-known in the art.The ionic strength of fasting state gastric juice is about 0.1M, and the ionic strength of fasting state intestinal juice is about 0.14.For example see " Characterization of Fluids from the Stomach andProximal Jejunum in Men and Women, " Pharm.Res. of Lindahl etc., 14 (4): 497-502 (1997).
The pH and the ionic strength that it is believed that testing liquid are more more crucial than specific chemical contents.Therefore, suitable pH and the ionic strength value Acid-Base that can pass through strong acid, highly basic, salt, single coupling or many couplings obtains many kinds combinations of (that is the corresponding salt of weak acid and this acid), simple substance and many protons electrolyte etc.Representational electrolyte solution can be but be not limited to: the NaCl solution of the HCl solution of the about 0.1M of the about 0.001-of concentration and the about 0.1M of the about 0.001-of concentration, with and composition thereof.For example, electrolyte solution can be but be not limited to: about 0.1M or rarer HCl, about 0.01M or rarer HCl, about 0.001M or rarer HCl, about 0.1M or rarer NaCl, about 0.01M or rarer NaCl, about 0.001M or rarer NaCl, with and composition thereof.In these electrolyte solutions, 0.01M HCl and/or 0.1M NaCl represent fasting Human Physiology condition most, belong to nearside gastrointestinal pH and ionic strength conditions.
0.001M the electrolyte concentration of HCl, 0.01M HCl and 0.1M HCl is respectively corresponding to pH=3, pH=2 and pH=1.For example, 0.01M HCl solutions simulate the typical acid condition that exists in the stomach.0.1M NaCl solution the rationally approximate of the ionic strength conditions that exists in comprising the whole human body of gastro-intestinal Fluid is provided, but the concentration that is higher than 0.1M can be used for feed condition in anthropomorphic dummy's the gastrointestinal tract.The exemplary solution that demonstrates salt, acid, alkali or its combination of desired pH value and ionic strength includes but not limited to, phosphoric acid/phosphate+sodium chloride, potassium chloride and calcium chloride, acetic acid/acetate+sodium chloride, potassium chloride and calcium chloride, carbonic acid/bicarbonate+sodium chloride, potassium chloride and calcium chloride, and citric acid/citrate+sodium chloride, potassium chloride and calcium chloride.
Redispersibility can detect with any suitable method known in the art.Referring to for example United States Patent (USP) 6, the embodiment part of 375,986 (Solid Dose Nanoparticulate Compositions Comprising aSynergistic Composition of a Polymeric Surface Stabilizer and DioctylSodium Sulfosuccinate).
6. the immunosuppressant composite of uniting use with other activating agent
The compositions that contains tacrolimus, sirolimus or its combination of the present invention can contain one or more chemical compounds that can be used for preventing organ rejection or treatment psoriasis or other immune diseases in addition.Compositions of the present invention can be prepared jointly with these other activating agents, or the present composition can be used jointly or use in proper order with described activating agent.The example of the medicine that can use jointly with tacrolimus and/or sirolimus or prepare jointly includes but not limited to cyclosporin, mycophenolic acid, alemtuzumab, mycophenolate mofetil, corticosteroid, glucocorticoid, doxycycline, interferon beta-1b, malononitrilamide FK778, azathioprine, Campath-1H, basiliximab and methotrexate.
D. compositions
The invention provides the compositions that comprises Nanoparticulate tacrolimus, sirolimus or its combination and at least a surface stabilizer.Surface stabilizer preferably adsorbs or associates in tacrolimus or the particulate surface of sirolimus.Useful herein surface stabilizer is not with tacrolimus or sirolimus granule or self chemical reaction takes place.Preferably, each molecule of surface stabilizer does not have the intermolecular cross-linking key basically.In another embodiment, compositions of the present invention can comprise two or more surface stabilizers.
The present invention also comprises the Nanoparticulate compositions that contains tacrolimus, sirolimus or its combination and one or more nontoxic physiology's acceptable carriers, auxiliary agent or mediator (being generically and collectively referred to as carrier).Described compositions can be formulated into and be used for intestinal and inject (for example intravenous, intramuscular or subcutaneous injection), peritoneal injection etc. outward.
1. immunosuppressive activity agent
The exemplary immunosuppressive activity agent that is used for the injectable dosage form of the present invention is tacrolimus and sirolimus.
Tacrolimus is also referred to as FK-506 or fujimycin 506, is a kind of 23 yuan macrolide.As used in this article, term " tacrolimus " comprises its analog and salt, and can be crystalline phase, amorphous phase, half hitch crystalline phase, half amorphous phase or its mixture.Tacrolimus may be with a kind of optically pure basically enantiomeric form, or exists with mixture, racemate or other form of enantiomer.The conventionally form of tacrolimus comprises solubilizing agent, as Cremophor , this is undesirable.
Sirolimus can be used as immunosuppressant and antifungal antibiotic, and its purposes is described in the following document: United States Patent (USP) 3,929,992,3,993,749 and 4,316,885 and belgian patent 877,700.This chemical compound only is slightly soluble in the water, i.e. 20 micrograms/mL, rapid hydrolysis when making moist.Because sirolimus is very unstable when running into aqueous medium, thus developed special injectable formulation so that be applied to the patient, as described in the European patent EP 041,795 those.This preparation is undesirable often, because common non-water solubilizer shows virose side effect.As used in this article, term " sirolimus " comprises its analog and salt, and can be crystalline phase, amorphous phase, hemihedral crystal phase, half amorphous phase or its mixture.Sirolimus may exist with a kind of form of optically pure enantiomer basically, and perhaps mixture, raceme or other form with enantiomer exists.
2. surface stabilizer
In the injectable formulation that contains tacrolimus, sirolimus or its combination of the present invention, can use the combination of more than one surface stabilizers.Suitable surface stabilizer includes but not limited to known organic or inorganic drug excipient.These excipient comprise various polymer, low-molecular-weight oligomer, natural product and surfactant.Surface stabilizer comprises nonionic, anionic, cationic, ion-type and amphoteric ionic surfactant.A kind of exemplary surface stabilizer that is used for injectable Nanoparticulate tacrolimus and/or nano-particle sirolimus preparation is the polyvidone polymer.
The representative example of surface stabilizer includes, but are not limited to hydroxypropyl emthylcellulose (now being called " hypromellose "), hydroxypropyl cellulose, polyvinylpyrrolidone, sodium lauryl sulphate, dioctylsulfosuccinat, gelatin, casein, lecithin (phospholipid), glucosan, Radix Acaciae senegalis, cholesterol, Tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ether (for example, polyglycol ether such as cetomacrogol 1000), castor oil derivatives, polyoxyethylene sorbitan fatty acid ester (for example, the commercially available Tween that gets , for example, Tween 20 With Tween 80 (ICI Speciality Chemicals)); (for example, Carbowaxes 3550 for Polyethylene Glycol With 934 (Union Carbide)), Myrj 45, silica sol, phosphate/ester, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl-cellulose, phthalic acid hypromellose, noncrystalline cellulose, Magnesiumaluminumsilicate, triethanolamine, polyvinyl alcohol (PVA), 4-(1,1,3, the 3-tetramethyl butyl) polymer of phenol and oxirane and formaldehyde (also claiming tyloxapol, alevaire and triton), poloxamer (for example, PluronicsF68 And F108 , it is the block copolymer of oxirane and expoxy propane); (for example, Tetronic 908 for poloxamines , also claim Poloxamine 908 , it is to add to ethylenediamine in proper order and the four functional blocks copolymers that form of deriving (BASF WyandotteCorporation, Parsippany, N.J.)) by expoxy propane and oxirane; Tetronic 1508 (T-1508) (BASFWyandotte Corporation), Triton X-200 (a kind of alkyl aryl polyether sulphonic acid ester, Rohnand Haas); Crodestas F-110 (mixture of sucrose stearate and sucrose distearate, Croda Inc.); To different Nonylphenoxy poly-((+)-2,3-Epoxy-1-propanol), be also referred to as Olin-1OG Or Surfactant 10-G (Olin Chemicals, Stamford, CT); Crodestas SL-40 (Croda, Inc.); And SA9OHCO (C 18H 37CH 2(CON (CH 3)-CH 2(CHOH) 4(CH 2OH) 2, Eastman Kodak Co.); Caprinoyl-N-methyl glucose amide (glucamide); Positive decyl (D-glycopyranoside; Positive decyl (D-pyrans maltoside; Dodecyl (D-glycopyranoside; Dodecyl (D-maltoside; Oenanthyl-N-methyl glucose amide; N-heptyl-(D-glycopyranoside; N-heptyl (D-sulfo-glucoside; N-hexyl (D-glycopyranoside; Nonanoyl-N-methyl glucose amide; Positive nonanoyl (D-glycopyranoside; Decoyl-N-methyl glucose amide; N-octyl-(D-glycopyranoside; Octyl group (D-sulfo-glycopyranoside; PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative; The PEG-vitamin A, PEG-vitamin E, lysozyme, the random copolymer of vinyl pyrrolidone and vinyl acetate etc.
The example of useful cationic surface stabilizer is including, but not limited to polymer, biopolymer, polysaccharide, cellulose material (cellulosics), alginate, phospholipid and non-polymeric chemical compound are such as the amphoteric ion type stabilizing agent, poly--n-picoline , chlorination anthryul pyridine , cationic phospholipid, chitosan, polylysine, polyvinyl imidazol, polybrene, bromination polymethyl methacrylate trimethylammonium bromide (PMMTMABr), hexyl desyl,a-phenyl phenacyl trimethylammonium bromide (HDMAB) and polyvinylpyrrolidone-2-dimethylamino-ethyl ester isobutene dimethyl sulfate.Other useful cationic stabilizing agents comprise but are not limited to, cationic lipid, sulfonium, rattle and quaternary ammonium compound are such as stearyl trimethyl ammonium chloride, benzyl two (2-chloroethyl) ethyl ammonium bromide, cocos nucifera oil trimethyl ammonium chloride or ammonium bromide, cocos nucifera oil methyl dihydroxy ethyl ammonium chloride or ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride or ammonium bromide, C 12-15Dimethyl hydroxyethyl ammonium chloride or ammonium bromide, coco dimethyl hydroxyethyl ammonium chloride or ammonium bromide, myristyl trimethyl ammonium methyl sulfate, lauryl dimethyl benzyl ammonium chloride or ammonium bromide, lauryl dimethyl (oxyethylene group) 4 ammonium chloride or ammonium bromide, N-alkyl (C 12-18) dimethyl benzyl ammonium chloride, N-alkyl (C 14-18) dimethyl benzyl ammonium chloride, N-myristyl dimethyl benzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C 12-14) dimethyl 1-naphthyl methyl ammonium chloride, trimethyl-ammonium halide, alkyl trimethyl ammonium salt and dialkyl dimethyl ammonium salt, lauryl trimethyl ammonium chloride, ethoxylation alkyl amido alkyl dialkyl ammonium salt and/or ethoxylation trialkyl ammonium salts, dialkyl benzene dialkylammonium chloride, N-DDAC, N-myristyl dimethyl benzyl ammonium chloride monohydrate, N-alkyl (C 12-14) dimethyl 1-naphthyl methyl ammonium chloride and dodecyl dimethyl benzyl ammonium chloride, dialkyl benzene alkyl ammomium chloride, lauryl trimethyl ammonium chloride, alkyl benzyl ammonio methacrylate, alkyl benzyl dimethyl ammonium bromide, C 12, C 15, C 17Trimethylammonium bromide, the dodecylbenzyl triethyl ammonium chloride, diallyl dimethyl ammoniumchloride (DADMAC), alkyl dimethyl ammonium chloride, the alkyl dimethyl ammonium halide, three (cetyl) ammonio methacrylate, the decyl trimethylammonium bromide, dodecyl triethyl group ammonium bromide, Tetradecyl Trimethyl Ammonium Bromide, methyl trioctylphosphine ammonium chloride (ALIQUAT336), POLYQUAT, tetrabutyl ammonium bromide, benzyltrimethylammonium bromide, cholinester (such as the cholinester of fatty acid), benzalkonium chloride, oronain (stearalkoniumchloride) compounds (such as stearyl trimethyl ammonium chloride and VARISOFT TA100) draws in department, cetyl pyridinium bromide  or pyridinium chloride , the halide salts of quaternised polyoxy ethyl alkylamine, MIRAPOL and ALKAQUAT (Alkaril Chemical Company), alkyl pyridine  salt; Amine, such as alkylamine, dialkylamine, alkanolamine, polyethylene polyamines, N, N-dialkyl aminoalkyl acrylate and vinylpyridine, amine salt, such as lauryl amine acetate, octadecylamine acetate, alkyl pyridine  salt and alkyl imidazole  salt, and amine oxide; Acid imide pyrroles  (imide azolinium) salt; Protonated season type acrylamide; Methylated season, the type polymer was as poly-[diallyldimethylammonium chloride] with gather [N-methyl ethylene pyridinium chloride ]; With cationic guar gum.
This exemplary cationic surface stabilizer and other useful cationic surface stabilizer are described in the following document: J.Cross and E.Singer, Cationic Surfactants:Analytical and Biological Evaluation (Marcel Dekker, 1994); P. and D.Rubingh (editor), Cationic Surfactants:Physical Chemistry (Marcel Dekker, 1991); And J.Richmond, Cationic Surfactants:Organic Chemistry, (MarcelDekker, 1990).
Non-polymeric surface stabilizer is any non-polymeric chemical compound, as the quaternary ammonium compound of benzalkonium chloride, carbon  chemical compound, rattle chemical compound, oxygen anchor chemical compound, halogen  chemical compound, cationic organo-metallic compound, quaternary phosphonium chemical compound, pyridine  chemical compound, aniline  chemical compound, ammonium compounds, hydroxyl ammonium compounds, uncle's ammonium compounds, secondary ammonium compounds, tertiary amine chemical compound and general formula NR1R2R3R4 (+).For general formula NR 1R 2R 3R 4The chemical compound of (+):
(i) R1-R4 is not CH 3
(ii) among the R1-R4 is CH 3
(iii) three among the R1-R4 are CH 3
(iv) R1-R4 is CH all 3
(v) two among the R1-R4 are CH 3, one among the R1-R4 is C 6H 5CH 2, and among the R1-R4 one is 7 or the alkyl chain of a carbon atom still less;
(vi) two among the R1-R4 are CH 3, one among the R1-R4 is C 6H 5CH 2, and among the R1-R4 one is the alkyl chain of 19 or more a plurality of carbon atoms;
(vii) two among the R1-R4 are CH 3, one among the R1-R4 is group C 6H 5(CH 2) n, n＞1 wherein;
(viii) two among the R1-R4 are CH 3, one among the R1-R4 is C 6H 5CH 2, and among the R1-R4 one contains at least one hetero atom;
(ix) two among the R1-R4 are CH 3, R1-R 4In one be C 6H 5CH 2, and among the R1-R4 one contains at least one halogen;
(x) two among the R1-R4 are CH 3, one among the R1-R4 is C 6H 5CH 2, and among the R1-R4 one contains at least one ring-type fragment;
(xi) two among the R1-R4 are CH 3, one among the R1-R4 is phenyl ring; Or
(xii) two among the R1-R4 are CH 3And two among the R1-R4 is pure aliphatic fragment.
These chemical compounds include but not limited to: docosyl benzyl dimethyl ammonium chloride, chlorination benzethonium, hexadecylpyridinium chloride , INCROQUAT TMC-80 ECONOL TM22, the dodecylbenzyl alkyl dimethyl ammonium chloride, hexadecyl benzyl dimethly ammonium chloride, cetyl trimethyl ammonium bromide, hexadecyltrimethylammonium chloride, cetyl hydrogen fluorine amine, chlorination chlorallyl hexamethylenetetramine (Quaternium-15), VARISOFT TA100 (Quaternium-5), dodecyl dimethyl ethylbenzylammonium chloride (Quaternium-14), Quaternium-22, Quaternium-26, the Quaternium-18 Strese Hofmann's hectorite., diformazan aminoethyl villaumite hydrochlorate, cysteine hydrochloride, diethanol ammonium POE (10) oleyl ether phosphate, diethanol ammonium POE (3) oleyl ether phosphate, Adeps Bovis seu Bubali base benzyl dimethyl ammonium chloride, the dimethyldioc-tadecylammonium bentonite, oronain draws in department, brominated phenododecinium bromide, denatonium benzoate, myristyl benzyl dimethyl ammonium chloride, Dodecyl trimethyl ammonium chloride, the ethylenediamine dihydrochloride, guanidine hydrochloride, pyridoxine hydrochloride, iofetamine hydrochloride, the hydrochloric acid meglumine, methylbenzethonium chloride, Tetradecyl Trimethyl Ammonium Bromide, the oil base trimethyl ammonium chloride, Polyquaternium-1, procaine hydrochloride, coco betaine, stearyl benzyl dimethyl ammonium bentonite, stearyl benzyl dimethyl ammonium Strese Hofmann's hectorite., octadecyl trihydroxy ethyl propane diamine two hydrofluorides, Adeps Bovis seu Bubali base trimethyl ammonium chloride and cetyl trimethyl ammonium bromide.
The great majority of these surface stabilizers are known drug excipient, Handbook of Pharmaceutical Excipients (The PharmaceuticalPress at The AmericanPharmaceutical Association and The Pharmaceutical Society of Great Britain combined publication, detailed description is arranged 2000), be incorporated herein by reference especially.
The polyvidone polymer
The polyvidone polymer is the exemplary surface stabilizer that is used to prepare injectable Nanoparticulate tacrolimus and/or nano-particle sirolimus preparation.The polyvidone polymer also claims " polyvidon (e) ", " povidonum ", " PVP " and " polyvinylpyrrolidone ", with Kollidon (BASF Corp.) and Plasdone (ISP Technologies, trade name Inc.) is sold.They are polydisperse macromole, and chemical name is 1-vinyl (ethenyl)-2-Pyrrolidone polymer and 1-vinyl (vinyl)-2-Pyrrolidone polymer.The polyvidone polymer is prepared to mean molecule quantity from about 10,000 to about 700,000 daltonian a series of products as commercial product.Will be as the surface modifier that is administered to mammiferous medical compounds, the molecular weight of polyvidone polymer must be less than about 40,000 dalton, because will be difficult to remove in body greater than 40,000 molecular weight.
The polyvidone polymer prepares with for example Reppe method, and comprising: (1) utilizes Reppe butadiene synthetic method, obtains 1 by acetylene and formaldehyde, the 4-butanediol; (2) 200 ℃ with 1, the dehydrogenation on copper of 4-butanediol forms gamma-butyrolacton; (3) make gamma-butyrolacton and ammonia react, generate ketopyrrolidine.Handle with acetylene subsequently, obtain vinylpyrrolidone monomer.At H 2O and NH 3Exist down, carry out polymerization by heating.Referring to The Merck Index, 10 ThEdition, pp.7581 (Merck﹠amp; Co., Rahway, NJ; 1983).
The polymer that the manufacture method of polyvidone polymer produces comprises the molecule that chain length does not wait, thereby the molecular weight difference.For every kind of specific commercially available grade that gets, the molecular weight of described molecule is approximately around a mean variation.Because be difficult to directly determine the molecular weight of polymer, so the most frequently used method with the different molecular weight grade separation is the K value of utilizing based on the viscosity measurement value.The K value of the polyvidone polymer of various different brackets is represented the function of mean molecule quantity, and it derives from the viscosity measurement value, and calculates according to the Fikentscher formula.
The weight-average value Mw of molecular weight is that method by the weight of measuring each molecule is as light scattering method and definite.Table 1 provides the molecular weight data of several commercially available polyvidone polymer that get, and described polyvidone polymer all is soluble.
Table 1
Polyvidone The K-value Mv (dalton) ** Mw (dalton) ** Mn (dalton) **
Plasdone C-15 17±1 7,000 10,500 3,000
Plasdone C-30 30.5±1.5 38,000 62,500 * 16,500
Kollidon 12 PF 11-14 3,900 2,000-3,000 1,300
Kollidon 17 PF 16-18 9,300 7,000-11,000 2,500
Kollidon 25 24-32 25,700 28,000-34,000 6,000
*Because molecular weight is greater than 40,000 dalton, this kind polyvidone polymer should not be used the surface stabilizer of the medical compounds of (that is injection) as intestinal outward.
*Mv is a viscosity-average molecular weight, and Mn is a number-average molecular weight, and Mw is a weight average molecular weight.Mw and Mn measure by light scattering and super centrifugal method, and Mv determines by viscosity measurement.
According to the data that provide in the table 1, the exemplary useful commercially available polyvidone polymer that gets includes but not limited to: Plasdone C-15 , Kollidon 12 PF , Kollidon 17 PF With Kollidon 25
3. the granularity of Nanoparticulate tacrolimus and sirolimus
As used in this article, according to determining granularity as the measured average particle size of regular particle size measuring technique well known to those skilled in the art.Described technology comprises for example sedimentation field flow fractionation, photon correlation spectrometry, light scattering and disc type centrifuging.
Immunosuppressant composite of the present invention comprises tacrolimus and/or sirolimus nano-particle, and its effective particle mean size is less than about 2000nm (promptly 2 microns).In other embodiments of the present invention, effective particle mean size of tacrolimus and sirolimus nano-particle is less than about 1900nm, less than about 1800nm, less than about 1700nm, less than about 1600nm, less than about 1500nm, less than about 1400nm, less than about 1300nm, less than about 1200nm, less than about 1100nm, less than about 1000nm, less than about 900nm, less than about 800nm, less than about 700nm, less than about 650nm, less than about 600nm, less than about 550nm, less than about 500nm, less than about 450nm, less than about 400nm, less than about 350nm, less than about 300nm, less than about 250nm, less than about 200nm, less than about 150nm, less than about 100nm,, as pass through light scattering method less than about 75nm or less than about 50nm, microtechnique or other appropriate method are measured.
" less than effective particle mean size of about 2000nm " is meant and calculates by weight, and at least 50% described tacrolimus, sirolimus or tacrolimus and the particulate granularity of sirolimus are less than effective meansigma methods, promptly less than about 2000nm.If " effectively particle mean size " less than about 1900nm, so, when measuring by aforesaid technology, the particulate size of the tacrolimus at least about 50%, sirolimus or tacrolimus and sirolimus is less than about 1900nm.For above-mentioned other granularity, so same.In other embodiment, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95% or at least about 99% tacrolimus, sirolimus or tacrolimus and the particulate granularity of sirolimus less than effective meansigma methods, promptly less than about 2000nm, less than about 1900nm, less than about 1800nm etc.
In the present invention, the D50 value of Nanoparticulate tacrolimus, sirolimus or tacrolimus and sirolimus compositions is by weight calculation, the granularity that 50% tacrolimus, sirolimus or tacrolimus and sirolimus granule are lower than.Similarly, D90 is by weight calculation, the granularity that 90% tacrolimus, sirolimus or tacrolimus and sirolimus granule are lower than.
4. the concentration of nanoparticulate immunosuppressive compounds and surface stabilizer
The relative populations of tacrolimus, sirolimus and its combination and one or more surface stabilizers can in very large range change.Separately the optimal number of component for example depends on the physics and the chemical property of selected surface stabilizer, as surface tension of the aqueous solution of hydrophile-lipophile balance (HLB), fusing point and stabilizing agent or the like.
Preferably, the concentration of tacrolimus, sirolimus or its combination can followingly change: the about 0.001wt% of about 99.5wt%-, the about 0.1wt% of about 95wt%-, or the about 0.5wt% of about 90wt%-, gross weight based on tacrolimus, sirolimus or its combination and at least a surface stabilizer does not comprise other excipient.From dosage and cost efficiency viewpoint, the higher concentration of active component is normally preferred.
Preferably, the concentration of surface stabilizer can followingly change: the about 99.999wt% of about 0.5wt%-, the about 99.9wt% of about 5.0wt%-, or the about 99.5wt% of about 10wt%-, based on the gross dry weight of activating agent and at least a surface stabilizer, do not comprise other excipient.
5. other drug excipient
Pharmaceutical composition of the present invention, according to route of administration and desirable dosage form, can also contain one or more binding agents, filler, lubricant, suspending agent, sweeting agent, correctives, antiseptic, buffer agent, wetting agent, disintegrating agent, effervescent and other excipient.These excipient are well-known in the art.
The example of filler is lactose monohydrate, Lactis Anhydrous and various starch; The example of binding agent is various celluloses and crosslinked polyvinylpyrrolidone, microcrystalline Cellulose such as Avicel PH101 and Avicel PH102, microcrystalline Cellulose and the microcrystalline Cellulose (ProSolvSMCC that silicifies TM).
Examples of suitable lubricants, it comprises the reagent that the flowability of wanting compressed powder is worked, and is silica sol, for example Aerosil 200, Talcum, stearic acid, magnesium stearate, calcium stearate and silica gel.
The example of sweeting agent is any natural or artificial sweetening agent, for example sucrose, xylitol, saccharin sodium, cyclamate, aspartame and acesulfame (acsulfame).The example of correctives is Magnasweet (MAFCO trade mark), bubble gum flavor and fruit flavor etc.
The example of antiseptic is other ester such as the butyl p-hydroxybenzoate, pure as ethanol or benzyl alcohol, phenolic compound such as phenol and quaternary ammonium compound such as benzalkonium chloride of potassium sorbate, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, benzoic acid and salt thereof, P-hydroxybenzoic acid.
Suitable diluent comprises medicinal acceptable inert filler, for example mixture of microcrystalline Cellulose, lactose, calcium hydrogen phosphate, saccharide and/or above-mentioned any material.The example of diluent comprises microcrystalline Cellulose, for example Avicel PH101 and Avicel PH102; Lactose, for example lactose monohydrate, Lactis Anhydrous and Pharmatose DCL21; Calcium hydrogen phosphate, for example Emcompress Mannitol; Starch; Sorbitol; Sucrose and glucose.
Suitable disintegrants comprises lightly crosslinked polyvinylpyrrolidone, Semen Maydis (corn) starch, potato starch, corn (maize) starch and modified starch, crosslinked sodium carboxymethyl cellulose, crospovidone (cross-povidone), primojel and composition thereof.
The example of effervescent is the effervescent counter pair, for example organic acid and carbonate or bicarbonate.Appropriate organic comprises for example citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid and alginic acid and anhydride and acid salt.Suitable carbonate and bicarbonate comprise for example sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate and arginine carbonate.Perhaps, can only there be sodium bicarbonate component in the effervescent counter pair.
6. injectable Nanoparticulate tacrolimus formulations
The invention provides the injectable nanoparticle formulations that contains tacrolimus, sirolimus or its combination, it comprises high drug level in low volume injected.Exemplary preparation comprises, counts based on w/w%:
Immunosuppressive activity agent: 1.0-50%
Surface stabilizer: 0.1-50%
Antiseptic: 0.05-0.25%
PH regulator agent: pH is about 6-about 7
Water: q.s.
Exemplary antiseptic comprises methyl parahydroxybenzoate (about 0.18%, based on w/w%), propyl p-hydroxybenzoate (about 0.02%, based on w/w%), phenol (about 0.5%, based on w/w%) and benzylalcohol (high to 2%v/v).Exemplary pH regulator agent is a sodium hydroxide, and exemplary liquid-carrier is an aseptic injection water.Other useful antiseptic, pH regulator agent and liquid-carrier are well-known in the art.
Active tacrolimus among the present invention or sirolimus may exist with a kind of form of optically pure enantiomer basically, and perhaps mixture, raceme or other form with enantiomer exists.Described immunosuppressant preferably is present in the injectable nanoparticle formulations of the present invention, and its quantity is the about 50mg of about 0.01mg-, and perhaps its quantity is the about 20mg of about 0.05mg-.
E. the method for preparing Nanoparticulate tacrolimus and/or sirolimus preparation
Use any suitable known method such as grinding, homogenize, precipitation or supercritical fluid particle generation technique in this area, can prepare Nanoparticulate tacrolimus and/or sirolimus compositions.The exemplary method of preparation nano-particle surfactant composition is described in United States Patent (USP) 5,145, in 684.The method for preparing the nano-particle surfactant composition has been described: United States Patent (USP) 5 in this external following document; 518; 187 (Method of Grinding Pharmaceutical Substances); United States Patent (USP) 5; 718; 388 (Continuous Method of Grinding Pharmaceutical Substances); United States Patent (USP) 5; 862; 999 (Method of Grinding Pharmaceutical Substances); United States Patent (USP) 5; 665; 331 (Co-Microprecipitation of Nano particulate PharmaceuticalAgents with Crystal Growth Modifiers); United States Patent (USP) 5; 662; 883 (Co-Microprecipitation of Nano particulate Pharmaceutical Agents with CrystalGrowth Modifiers); United States Patent (USP) 5; 560; 932 (Microprecipitation of Nanoparticulate Pharmaceutical Agents); United States Patent (USP) 5; 543; 133 (Process ofPreparing X-Ray Contrast Compositions Containing Nanoparticles); United States Patent (USP) 5; 534; 270 (Method of Preparing Stable Drug Nanoparticles); United States Patent (USP) 5; 510; 118 (Process of Preparing Therapeutic Compositions ContainingNanoparticles) and United States Patent (USP)s 5; 470; 583 (Method of Preparing NanoparticleCompositions Containing Charged Phospholipids to Reduce Aggregation), it all is incorporated herein by reference especially.
Formed Nanoparticulate tacrolimus and/or sirolimus compositions or dispersion may be used with the form of solid, semisolid or liquid dosage form preparation, for example liquid dispersion, gel, aerosol, ointment, emulsifiable paste, controlled release preparation, fast thawing preparation, freeze-dried preparation, tablet, capsule, delayed release preparation, prolongation delivery formulations, delivery formulations, the mixed type of pulsing releasing agent and controlled release preparation etc. immediately.In the present invention, injectable dosage form is preferred.
In another aspect of this invention, provide a kind of method for preparing injectable nano-particle immunosuppressant preparation of the present invention.Said method comprising the steps of: (1) in liquid dispersion medium with the dispersion of tacrolimus, sirolimus or its combination of desired amount; (2) with mechanical means with the particle size reduction of tacrolimus, sirolimus or its combination to effective particle mean size less than about 2000nm.Before the particle size reduction of activating agent, among or afterwards, surface stabilizer can be added in the disperse medium.In one embodiment, described surface stabilizer is that molecular weight is less than about 40,000 daltonian polyvidone polymer.During the particle size reduction process, liquid dispersion medium can be maintained the physiological pH level, for example about 3.0-about 8.0; During the particle size reduction process, more preferably about 5.0-about 7.5.In another embodiment, the disperse medium that is used for the particle size reduction process is an aqueous.
Use the particle size reduction method, with the particle size reduction of immunosuppressant to effective particle mean size less than about 2000nm.For the particle size reduction of tacrolimus or sirolimus immunosuppressant provides the effective ways of mechanical force to comprise ball milling, medium milling and homogenize, for example utilize Microfluidizer (Microfluidics Corp.).Ball milling is a kind of low-yield Ginding process that uses abrasive media, medicine, stabilizing agent and liquid.Material is placed in the grinding container with optimum speed rotation, makes the abrasive media stepwise fall and makes drug particle size reduce by bump.Used medium must have high density, is that quality by gravity and abrasive media provides because be used for the energy of particle size reduction.
Medium milling is the high-energy Ginding process.Medicine, stabilizing agent and liquid are placed in the bin recirculation in the cell that contains medium and rotating shaft/impeller.Medium is stirred in rotating shaft, and it is impacted medicine and shear action, thereby has reduced the granularity of medicine.
Homogenize is a kind of technology of not using abrasive media.Medicine, stabilizing agent and liquid (perhaps medicine and liquid, stabilizing agent adds behind particle size reduction) are formed process-stream, and it is advanced in the process section, and described process section is at Microfluidizer In called be interaction chamber (InteractionChamber).Pending product is introduced in the pump, releases then.Microfluidizer Priming valve the air in the pump is discharged.In case be full of product in the pump, priming valve is closed and product is urged and passes interaction chamber.The geometry of interaction chamber produces strong shearing, impact and cavitation power, and this is the reason of particle size reduction.Specifically, in interaction chamber, the product of pressurized is divided into two bursts of logistics and is accelerated to high speed.Formed jet is penetrated mutually each other in interaction zone subsequently and is collided.Formed product has very thin and uniform grain sizes or drop size.Microfluidizer Also provide heat exchanger so that the product cooling.United States Patent (USP) 5,510,118 have mentioned use Microfluidizer Method, this patent specially is incorporated herein by reference.
Immunosuppressant can be added to the undissolved basically liquid medium of immunosuppressant therein, thereby form pre-composition.Surface stabilizer may reside in the pre-composition, and perhaps it can add in the pharmaceutical dispersions behind particle size reduction.By making pre-composition experience plant equipment average tacrolimus or sirolimus particle size reduction in the dispersion are arrived less than about 2000nm, thereby can directly use this pre-composition.Preferably when using ball mill to grind, directly use pre-composition.Perhaps, use suitable stirring, for example Cowles type blender can be dispersed in immunosuppressant and at least a surface stabilizer in the liquid medium, until the dispersion of observing homogenizing, does not wherein have macroscopic big agglomerate.Preferably when using recirculation medium grinding machine to grind, pre-composition stands a kind of so pre-grinding dispersion steps.
Be used to make the plant equipment of tacrolimus or sirolimus particle size reduction can take the form of disperse mill.Suitable disperse mill comprises ball mill, vertical grinder (attritor mill), vibrating mill, medium grinding machine such as sand mill and ball mill.The medium grinding machine is preferred, because need relatively short milling time that the reducing of granularity of expectation is provided.For the medium grinding machine, the apparent viscosity of pre-composition is preferably about 1000 centipoises of about 100-, and for ball milling, the apparent viscosity of pre-composition is preferably about 1 until about 100 centipoises.Such scope often provides the optimum balance between effective particle size reduction and the erosion medium resistance.
Milling time can in very large range change, and this depends primarily on specific plant equipment and selected processing conditions.For ball mill, may require maximum 5 days or more longer process time.Perhaps, by means of high shear medium grinding machine, be possible (time of staying be 1 minute until a few hours) process time that is shorter than 1 day.
Under the not obvious temperature that makes the immunosuppressant molecular degradation, can make the particulate particle size reduction of tacrolimus or sirolimus.Usually preferred processing temperature is less than about 40 ℃ less than about 30-.If desired, can cool off process equipment by traditional cooling device.For example, consider by chuck or will the grinding machine chamber immerse in the frozen water control temperature.Usually, method of the present invention is to carry out easily safely and under the condition of effective tonnage in ambient temperature with for Ginding process.The environment tonnage be ball mill, vertical grinder and vibrating mill the typical case use.
Abrasive media
The abrasive media of particle size reduction step can be selected from rigid media, and preferred spherical or granular, average-size is more preferably less than about 1mm less than about 3mm.This medium makes us can providing desirably the granule of the present invention with shorter process time and makes milling apparatus that less wearing and tearing be arranged.Do not think that the material selection of abrasive media is crucial.Zirconium oxide is as being exemplary grinding-material with the 95%ZrO of stabilized magnesium hydroxide, Zirconium orthosilicate., pottery, rustless steel, titanium dioxide, aluminium oxide, with the stable 95%ZrO of yttrium, glass grinding media and polymeric grinding media.
Abrasive media can comprise granule, and it preferably is globular basically, and for example beadlet is made up of polymer resin or other suitable material basically.Perhaps, abrasive media can comprise the core with polymer resin coating adhered thereto.The density of polymer resin can be the about 3.0g/cm of about 0.8- 3
Usually, suitable polymer resin is at chemistry and physically be inert, is substantially free of metal, solvent and monomer, and has enough hardness and fragility, makes it can avoid cracked or pulverize during grinding.Suitable polymer resin comprises crosslinked polystyrene, as the polystyrene with divinyl benzene crosslinked; Styrol copolymer; Merlon; Polyacetals, for example Delrin (E.I.du Pontde Nemours and Co.); Vinyl chloride-base polymer and copolymer; Polyurethane; Polyamide; Poly-(tetrafluoroethene), for example Teflon (E.I.du Pont de Nemours and Co.) and other fluoropolymer; High density polyethylene (HDPE); Polypropylene; Cellulose ether and ester, for example cellulose acetate; Poly-hydroxyl methacrylate; The poly-hydroxyethyl acrylate; And siloxane-containing copolymer, for example polysiloxanes etc.Polymer can be biodegradable.Exemplary biodegradable polymer comprises copolymer, polyanhydride, poly-(hydroxyethyl methylacrylate), poly-(iminocarbonic ester), poly-(N-acyl group hydroxyproline) ester, poly-(N-palmityl hydroxyproline) ester, ethylene-vinyl acetate copolymer, poly-(ortho esters), poly-(caprolactone) and poly-(phosphonitrile) of poly-(lactide), poly-(Acetic acid, hydroxy-, bimol. cyclic ester), lactide and Acetic acid, hydroxy-, bimol. cyclic ester.For biodegradable polymer, the pollution of medium itself can advantageously be carried out the body intracellular metabolic and become biological acceptable product, and it can be discharged from health.
The abrasive media preferred size is the about 3mm of about 0.01-.For fine gtinding, the gravel size decision ground of abrasive media is the about 2mm of about 0.02-, more preferably is the about 1mm of about 0.03-.
In preferred Ginding process, make granule continuously.This method comprises active tacrolimus or sirolimus is joined in the grinding chamber continuously, and described chemical compound is contacted with abrasive media, makes particle size reduction simultaneously in grinding chamber, and takes out the active nano granule continuously from grinding chamber.
In secondary operations, utilize conventional isolation technics, for example utilize simple filtration, grade, abrasive media is separated with Nanoparticulate tacrolimus that ground or sirolimus through granular membrane or filter mesh sieve.Also can use other isolation technics for example centrifugal.
Sterile product is made
The demand for development of injectable compositions is made sterile product.Manufacture method of the present invention is similar with the typical known manufacturing methods that is used for sterile suspension.The manufacturing process flow diagram of typical sterile suspension is as follows:
(medium adjusting)
↓
Be mixed
↓
Particle size reduction
↓
Bottling
(lyophilization) and/or (terminal sterilization)
Shown in optional step in the bracket, the method and/or the germ-resistant method of particle size reduction depended in some processing.For example, for the Ginding process of working medium not, do not need medium to regulate.If terminal sterilization is not feasible,, then can use sterile-processed because chemistry and/or physical instability cause.
F. Therapeutic Method
Another aspect of the present invention provides a kind of injectable Nanoparticulate tacrolimus of the present invention or sirolimus preparation of using that the mammal that comprises the people is treated with prevention organ rejection or treatment psoriasis or other immune diseases.Said method comprising the steps of: the injectable Nanoparticulate tacrolimus or the sirolimus preparation of treatment effective dose of the present invention are applied to the experimenter so that form subcutaneous or intramuscular storage point in the patient.Along with the time, described storage is put lentamente release of active agent and is provided long-term treatment or treatment psoriasis or other immune diseases to allogeneic organ receiver.The storage point preparation of tacrolimus or sirolimus can provide immunosuppressant therapy to reach 1 year, if require like this.
In other embodiments of the present invention, injectable storage point Nanoparticulate tacrolimus, sirolimus or its combination compositions provide the treatment level of medicine to reach up to about 1 week, up to about 2 weeks, up to about 3 weeks, up to about 4 weeks, up to about 5 weeks, up to about 6 weeks, up to about 7 weeks, up to about 8 weeks, up to about 9 weeks, up to about 10 weeks, up to about 11 weeks, up to about 12 weeks, up to about January, up to about February, up to about March, up to about April, up to about May, up to about June, up to about July, up to about August, up to about JIUYUE, up to about October, up to about November or up to about 1 year.
The special beneficial feature of the present invention be injectable Nanoparticulate tacrolimus of the present invention, sirolimus or tacrolimus and sirolimus preparation can be injected into become storage point in patient's body and eliminated use polyoxyethylene (60) castor oil hydrogenated (HCO-60) and/or Polysorbate such as polyoxyethylene sorbitan monoleate as the needs of solubilizing agent.In addition, injectable formulation of the present invention can provide tacrolimus, sirolimus or its combination of high concentration so that realize the long-term treatment effect in storage point induction system.
Ordinary skill will be understood that the effective dose of tacrolimus, sirolimus or its combination can be determined by rule of thumb and can use with pure form that wherein, described form exists with medicinal acceptable salt, ester or prodrug form.Therefore, selected dosage level depends on effectiveness, desired therapeutic persistent period and the other factors of desired therapeutic effect, route of administration, the tacrolimus of being used, sirolimus or its combination.
The dosage device compositions can contain its these quantity of measuring (submultiples) approximately, and described amount approximately can be used to constitute daily dose.Yet should be appreciated that for any specific patient, concrete dosage level will depend on multiple factor: the cell that realize or the type of physiological responses and degree; The concrete agent that uses or the activity of compositions; Concrete agent or the compositions used; Patient's age, body weight, general health situation, sex and diet; The drainage rate of time of application, route of administration and medicine; The persistent period of treatment; With associating of concrete agent or the medicine that uses simultaneously; And the similar factor of knowing in the medical domain.
* * * * *
Provide following examples in order to explanation the present invention.Yet should be appreciated that the spirit and scope of the present invention are not limited to actual conditions or the details described among these embodiment, and only should be subjected to the restriction of the scope of claim.All lists of references that provide herein comprise United States Patent (USP), all are incorporated herein by reference especially.
Embodiment
Embodiment 1
The purpose of this embodiment is that preparation is suitable for the Nanoparticulate tacrolimus formulations as injectable dosage form.Fig. 1 has shown the 100X light micrograph that the employing phase place optical technology of the tacrolimus that does not grind is taken.
10% (w/w) tacrolimus (Camida LLC) aqueous dispersion that is combined with 2% (w/w) polyvinylpyrrolidone (PVP) K29/32 and 0.05% (w/w) dioctylsulfosuccinat (DOSS) is at NanoMill 0.01 (NanoMill Systems, King of Prussia, PA; Referring to for example United States Patent (USP) 6,431,478) the 10ml grinding chamber in 500 microns PolyMill Abrasive media (DowChemical, 89% medium useful load) grinds together.Mixture was ground 60 minutes under the speed of 2500rpm.
After the grinding, in deionized distilled water, use the particulate granularity of tacrolimus after Horiba LA910 particle size analyzer is measured grinding.The granularity of the tacrolimus after the initial average grinding is 192nm, and D50 is 177nm, and D90 is 278nm, and is as shown in table 1.Fig. 2 has shown the 100X light micrograph that the employing phase place optical technology of the tacrolimus after grinding is taken.After＜15 ℃ of following 1 weeks of cold preservation, in measuring the second time in distilled water, average tacrolimus granularity is 245nm, and D50 is 219nm, and D90 is 374nm.Fig. 3 has shown the 100X light micrograph that the employing phase place optical technology of the tacrolimus after the grinding after 1 week of cold preservation is taken.
Table 1
Sample Particle mean size (nm) D50 granularity (nm) D90 granularity (nm)
Initial tacrolimus/PVP/DOSS sample 192 177 278
Tacrolimus/PVP/DOSS sample is after 1 week of cold preservation 245 219 374
The result shows and successfully prepared stabilized nano granule tacrolimus formulations, because the particle mean size that obtains is 192nm, and observes minimum granularity after storing and increases.
Embodiment 2
The purpose of this embodiment is that preparation is suitable for the Nanoparticulate tacrolimus formulations as injectable dosage form.
10% (w/w) tacrolimus (Camida LLC) aqueous dispersion that is combined with 2%PVP K12 and 0.15% NaTDC is at NanoMill 0.01 (NanoMill Systems, King ofPrussia, PA; Referring to for example United States Patent (USP) 6,431,478) the 10ml grinding chamber in 500 microns PolyMill Abrasive media (Dow Chemical, 89% medium useful load) grinds together.Mixture was ground 150 minutes under the speed of 2500rpm.
After the grinding, in deionized distilled water, use the particulate granularity of tacrolimus after Horiba LA910 particle size analyzer is measured grinding.The granularity of the tacrolimus after the average grinding is 329nm, and D50 is 303nm, and D90 is 466nm.Fig. 4 has shown the 100X light micrograph that the employing phase place optical technology of the tacrolimus after grinding is taken.
The result shows and has successfully prepared stabilized nano granule tacrolimus formulations, because the particle mean size that obtains is 329nm.
Embodiment 3
The purpose of this embodiment is that preparation is suitable for the Nanoparticulate tacrolimus formulations as injectable dosage form.
Be combined with 3% (w/w) Pluronic 20% (w/w) tacrolimus (Camida LLC) aqueous dispersion of S630 and 0.05% (w/w) DOSS is at NanoMill 0.01 (NanoMill Systems, Kingof Prussia, PA; Referring to for example United States Patent (USP) 6,431,478) the 10ml grinding chamber in 500 microns PolyMill Abrasive media (Dow Chemical, 89% medium useful load) grinds together.Mixture was ground 60 minutes under the speed of 2500rpm.The 100X light micrograph that has shown the employing phase place optical technology shooting of the tacrolimus after grinding among Fig. 5.
After the grinding, in deionized distilled water, use the particulate granularity of tacrolimus after Horiba LA910 particle size analyzer is measured grinding.The granularity of the tacrolimus after the initial average grinding is 171nm, and D50 is 163nm, and D90 is 230nm, as shown in the following Table 2.After＜15 ℃ of following 1 weeks of cold preservation, in measuring the second time in distilled water, average tacrolimus granularity is 194nm, and D50 is 180nm, and D90 is 279nm.Shown the 100X light micrograph that the employing phase place optical technology of the tacrolimus after the grinding after a week is stored in cold preservation is taken among Fig. 6.
Table 2
Sample Particle mean size (nm) D50 granularity (nm) D90 granularity (nm)
Initial tacrolimus/Pluronic The S630/DOSS sample 171 163 230
Tacrolimus/Pluronic The S630/DOSS sample is after 1 week of cold preservation 194 180 279
The result shows and successfully prepared stabilized nano granule tacrolimus formulations, because the particle mean size that obtains is 171nm, and observes minimum granularity after storing and increases.
Embodiment 4
The purpose of this embodiment is that preparation is suitable for the Nanoparticulate tacrolimus formulations as injectable dosage form.
10% (w/w) tacrolimus (Camida LLC) aqueous dispersion that is combined with 2% hydroxypropyl cellulose (HPC-SL) and 0.1% (w/w) DOSS is at NanoMill 0.01 (NanoMill Systems, King of Prussia, PA; Referring to for example United States Patent (USP) 6,431,478) the 10ml grinding chamber in 500 microns PolyMill Abrasive media (Dow Chemical, 89% medium useful load) grinds together.Mixture was ground 150 minutes under the speed of 2500rpm.The 100X light micrograph that has shown the employing phase place optical technology shooting of the tacrolimus after grinding among Fig. 7.
After the grinding, in deionized distilled water, use the particulate granularity of tacrolimus after Horiba LA910 particle size analyzer is measured grinding.The granularity of the tacrolimus after the average grinding is 389nm, and D50 is 328nm, and D90 is 614nm.
The result shows and has successfully prepared stabilized nano granule tacrolimus formulations, because the particle mean size that obtains is 389nm.
Embodiment 5
The purpose of this embodiment is that preparation is suitable for the Nanoparticulate tacrolimus formulations as injectable dosage form.
5% (w/w) tacrolimus (Camida LLC) aqueous dispersion that is combined with 1% (w/w) HPC-SL and 0.15% (w/w) DOSS is at NanoMill 0.01 (NanoMill Systems, King ofPrussia, PA; Referring to for example United States Patent (USP) 6,431,478) the 10ml grinding chamber in 500 microns PolyMill Abrasive media (Dow Chemical, 89% medium useful load) grinds together.Mixture was ground 90 minutes under the speed of 5500rpm.The 100X light micrograph that has shown the employing phase place optical technology shooting of the tacrolimus after grinding among Fig. 8.
After the grinding, in deionized distilled water, use the particulate granularity of tacrolimus after Horiba LA910 particle size analyzer is measured grinding.The granularity of the tacrolimus after the initial average grinding is 169nm, and D50 is 160nm, and D90 is 225nm, as shown in the following Table 3.After 12 days, in measuring the second time in distilled water, average tacrolimus granularity is 155nm＜15 ℃ of following cold preservations, and D50 is 138nm, and D90 is 216nm.Shown the 100X light micrograph that the employing phase place optical technology of tacrolimus after cold preservation is stored 12 days after grinding taken among Fig. 9.
Table 3
Sample Particle mean size (nm) D50 granularity (nm) D90 granularity (nm)
Initial tacrolimus/HPC-SL/DOSS sample 169 160 225
Tacrolimus/HPC-SL/DOSS sample, cold preservation is after 12 days 155 138 216
The result shows and has successfully prepared stabilized nano granule tacrolimus formulations, because the particle mean size that obtains is 169nm, and observes minimum change of granularity after storing.
Embodiment 6
The purpose of this embodiment is that preparation is suitable for the Nanoparticulate tacrolimus formulations as injectable dosage form.
5% (w/w) tacrolimus (Camida LLC) aqueous dispersion that is combined with 1% (w/w) HPC-SL and 0.1% (w/w) NaTDC is at NanoMill 0.01 (NanoMill Systems, King ofPrussia, PA; Referring to for example United States Patent (USP) 6,431,478) the 10ml grinding chamber in 500 microns PolyMill Abrasive media (Dow Chemical, 89% medium useful load) grinds together.Mixture was ground 75 minutes under the speed of 5500rpm.The 100X light micrograph that has shown the employing phase place optical technology shooting of the tacrolimus after grinding among Figure 10.
After the grinding, in deionized distilled water, use the particulate granularity of tacrolimus after Horiba LA 910 particle size analyzers are measured grinding.The granularity of the tacrolimus after the initial average grinding is 1780nm, and D50 is 220nm, and D90 is 6665nm, as shown in the following Table 4.After 12 days, in measuring the second time in distilled water, average tacrolimus granularity is 65100nm＜15 ℃ of following cold preservations, and D50 is 31252nm, and D90 is 175813nm.Shown the 100X light micrograph that the employing phase place optical technology of tacrolimus after cold preservation is stored 12 days after grinding taken among Figure 11.
Table 4
Sample Particle mean size (nm) D50 granularity (nm) D90 granularity (nm)
Initial tacrolimus/HPC-SL/ NaTDC 1780 220 6665
Tacrolimus/HPC-SL/ deoxycholic acid sodium sample, cold preservation is after 12 days 65100 31252 175813
The result shows and does not successfully prepare stabilized nano granule tacrolimus formulations that because after storage 12 days, observing tangible granularity increases and caking phenomenon.In addition, the 100X light micrograph of the shooting of the employing phase place optical technology after grinding has also shown big, possible " grinding " crystalline existence.
Embodiment 7
The purpose of this embodiment is that preparation is suitable for the Nanoparticulate tacrolimus formulations as injectable dosage form.
10% (w/w) tacrolimus (Camida LLC) aqueous dispersion that is combined with 2% (w/w) hydroxypropyl emthylcellulose (HPMC) and 0.05% (w/w) DOSS is at NanoMill 0.01 (NanoMillSystems, King of Prussia, PA; Referring to for example United States Patent (USP) 6,431,478) the 10ml grinding chamber in 500 microns PolyMill Abrasive media (Dow Chemical, 89% medium useful load) grinds together.Mixture was ground 60 minutes under the speed of 2500rpm.The 100X light micrograph that has shown the employing phase place optical technology shooting of the tacrolimus after grinding among Figure 12.
After the grinding, in deionized distilled water, use the particulate granularity of tacrolimus after Horiba LA 910 particle size analyzers are measured grinding.The granularity of the tacrolimus after the initial average grinding is 215nm, and D50 is 196nm, and D90 is 311nm, as shown in the following Table 5.After＜15 ℃ of following 1 weeks of cold preservation, in measuring the second time in distilled water, average tacrolimus granularity is 227nm, and D50 is 206nm, and D90 is 337nm.Shown the 100X light micrograph that the employing phase place optical technology of the tacrolimus after the grinding after a week is stored in cold preservation is taken among Figure 13.
Table 5
Sample Particle mean size (nm) D50 granularity (nm) D90 granularity (nm)
Initial tacrolimus/HPMC/DOSS 215 196 311
Tacrolimus/HPMC/DOSS sample is after 1 week of cold preservation 227 206 337
The result shows and successfully prepared stabilized nano granule tacrolimus formulations, because the particle mean size that obtains is 215nm, and observes minimum granularity after storing and increases.
Embodiment 8
The purpose of this embodiment is that preparation is suitable for the Nanoparticulate tacrolimus formulations as injectable dosage form.
10% (w/w) tacrolimus (Camida LLC) and 2% (w/w) Pluronic The aqueous dispersion of F108 is at NanoMill 0.01 (NanoMill Systems, King of Prussia, PA; Referring to for example United States Patent (USP) 6,431,478) the 10ml grinding chamber in 500 microns PolyMill Abrasive media (Dow Chemical, 89% medium useful load) grinds together.Mixture was ground 60 minutes under the speed of 2500rpm.The 100X light micrograph that has shown the employing phase place optical technology shooting of the tacrolimus after grinding among Figure 14.
After the grinding, in deionized distilled water, use the particulate granularity of tacrolimus after Horiba LA 910 particle size analyzers are measured grinding.The granularity of the tacrolimus after the initial average grinding is 237nm, and D50 is 212nm, and D90 is 355nm, as shown in the following Table 6.After＜15 ℃ of following 1 weeks of cold preservation, in measuring the second time in distilled water, average tacrolimus granularity is 332nm, and D50 is 306nm, and D90 is 467nm.Shown the 100X light micrograph that the employing phase place optical technology of the tacrolimus after the grinding after a week is stored in cold preservation is taken among Figure 15.
Table 6
Sample Particle mean size (nm) D50 granularity (nm) D90 granularity (nm)
Initial tacrolimus/Pluronic F108 237 212 355
Tacrolimus/Pluronic The F108 sample is after 1 week of cold preservation 332 306 467
The result shows and successfully prepared stabilized nano granule tacrolimus formulations, because the particle mean size that obtains is 237nm, and observes minimum granularity after storing and increases.
Embodiment 9
The purpose of this embodiment is that preparation is suitable for the Nanoparticulate tacrolimus formulations as injectable dosage form.
10% (w/w) tacrolimus (Camida LLC) and 2% (w/w) Tween 80 aqueous dispersion is at NanoMill 0.01 (NanoMill Systems, King of Prussia, PA; Referring to for example United States Patent (USP) 6,431,478) the 10ml grinding chamber in 500 microns PolyMill Abrasive media (DowChemical, 89% medium useful load) grinds together.Mixture was ground 60 minutes under the speed of 2500rpm.The 100X light micrograph that has shown the employing phase place optical technology shooting of the tacrolimus after grinding among Figure 16.
After the grinding, in deionized distilled water, use the particulate granularity of tacrolimus after Horiba LA 910 particle size analyzers are measured grinding.The granularity of the tacrolimus after the initial average grinding is 208nm, and D50 is 191nm, and D90 is 298nm, as shown in the following Table 7.After＜15 ℃ of following 1 weeks of cold preservation, in measuring the second time in distilled water, average tacrolimus granularity is 406nm, and D50 is 348nm, and D90 is 658nm.Shown the 100X light micrograph that the employing phase place optical technology of the tacrolimus after the grinding after a week is stored in cold preservation is taken among Figure 17.
Table 7
Sample Particle mean size (nm) D50 granularity (nm) D90 granularity (nm)
Initial tacrolimus/Tween 80 208 191 298
Tacrolimus/Tween 80 samples are after 1 week of cold preservation 406 348 658
The result shows that this preparation may not be preferred, because after storing for 1 week, the tacrolimus granularity almost doubles.Yet granularity is still in less than 2 microns preferred size.
Embodiment 10
The purpose of this embodiment is to describe the injectable dosage form that contains Nanoparticulate tacrolimus and sirolimus.
By being combined with nano-particle sirolimus compositions, any Nanoparticulate tacrolimus formulations described in embodiment 1-5 or the 7-9 can prepare the injectable compositions that contains Nanoparticulate tacrolimus and nano-particle sirolimus.As described in US 20030054042 (Stabilization ofchemical compounds using nanoparticulate formulations), can prepare nano-particle sirolimus compositions.
* * * *
To those skilled in the art, it is evident that under the conditions without departing from the spirit and scope of the present invention, can in method and composition of the present invention, carry out many changes and variation.Thereby, the invention is intended to contain change of the present invention and variation, prerequisite be they fall into claims with and the scope of equivalent in.

Claims (30)

1. injectable nanoparticle formulations, it comprises:
(a) effective particle mean size is less than the tacrolimus granule of about 2000nm; With
(b) at least a surface stabilizer.
2. the compositions of claim 1 also comprises sirolimus granule and the surface stabilizer of effective particle mean size less than about 2000nm, and wherein the sirolimus surface stabilizer can be identical or different with the tacrolimus surface stabilizer.
3. claim 1 or 2 compositions, wherein tacrolimus is selected from crystalline phase, amorphous phase, hemihedral crystal phase, half amorphous phase and its mixture.
4. each compositions among the claim 1-3, wherein the particulate effective particle mean size of Nanoparticulate tacrolimus is selected from less than about 1900nm, less than about 1800nm, less than about 1700nm, less than about 1600nm, less than about 1500nm, less than about 1400nm, less than about 1300nm, less than about 1200nm, less than about 1100nm, less than about 1000nm, less than about 900nm, less than about 800nm, less than about 700nm, less than about 650nm, less than about 600nm, less than about 550nm, less than about 500nm, less than about 450nm, less than about 400nm, less than about 350nm, less than about 300nm, less than about 250nm, less than about 200nm, less than about 150nm, less than about 100nm, less than about 75nm with less than about 50nm.
5. each compositions among the claim 1-4, wherein when patient is given in injection, forms subcutaneous or intramuscular storage point so that the release of permanent immunity inhibitor.
6. each compositions among the claim 1-5, wherein said composition also comprises one or more medicinal acceptable excipient, carrier or its combination.
7. each compositions among the claim 1-6, wherein the content of at least a surface stabilizer is selected from following: the about 99.999wt% of about 0.5wt%-, about 99.9wt% of about 5.0wt%-and the about 99.5wt% of about 10wt%-, based on the gross dry weight of tacrolimus and at least a surface stabilizer, do not comprise other excipient.
8. each compositions among the claim 1-7, wherein the content of tacrolimus is selected from following: the about 0.001wt% of about 99.5wt%-, the about 0.1wt% of about 95wt%-, with the about 0.5wt% of about 90wt%-, based on the gross weight of tacrolimus and at least a surface stabilizer, do not comprise other excipient.
9. each compositions among the claim 1-8, it comprises at least two kinds of surface stabilizers.
10. each compositions among the claim 1-9, wherein surface stabilizer is selected from anionic surface stabilizing agent, cationic surface stabilizing agent, amphion surface stabilizer, non-ionic surface stabilizing agent and ion surface stabilizing agent.
11. each compositions among the claim 1-10, wherein at least a surface stabilizer is selected from hexadecylpyridinium chloride , gelatin, casein, phospholipid, glucosan, glycerol, Radix Acaciae senegalis, cholesterol, Tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ether, castor oil derivatives, the polyoxyethylene sorbitan fatty acid ester, Polyethylene Glycol, Dodecyl trimethyl ammonium chloride, Myrj 45, silica sol, phosphate/ester, sodium lauryl sulphate, carboxymethylcellulose calcium, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl-cellulose, the phthalic acid hypromellose, noncrystalline cellulose, Magnesiumaluminumsilicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1,3,3-tetramethyl butyl) polymer of phenol and oxirane and formaldehyde, poloxamer; The mixture of poloxamines, charged phospholipid, dioctylsulfosuccinat, sodium sulfosuccinate dialkyl, sodium lauryl sulphate, alkyl aryl polyether sulphonic acid ester, sucrose stearate and sucrose distearate, to different Nonylphenoxy poly-((+)-2,3-Epoxy-1-propanol), caprinoyl-N-methyl glucose amide; Positive decyl β-D-glycopyranoside; Positive decyl β-D-pyrans maltoside; Dodecyl β-D-glycopyranoside; Dodecyl β-D-maltoside; Oenanthyl-N-methyl glucose amide; N-heptyl-β-D-glycopyranoside; N-heptyl β-D-sulfo-glucoside; N-hexyl β-D-glycopyranoside; Nonanoyl-N-methyl glucose amide; N-nonyl β-D-glycopyranoside; Decoyl-N-methyl glucose amide; N-octyl-β-D-glycopyranoside; Octyl group β-D-sulfo-glycopyranoside; Lysozyme, PEG-phospholipid, the PEG-cholesterol, the PEG-cholesterol derivative, the PEG-vitamin A, the PEG-vitamin E, the random copolymer of vinyl acetate and vinyl pyrrolidone, cation type polymer, cationic biopolymer, cationic polysaccharide, cationic cellulose material, cationic alginate, cationic non-polymeric chemical compound, cationic phospholipid, cationic lipid, the polymethyl methacrylate trimethylammonium bromide, sulfonium compound, polyvinylpyrrolidone-2-dimethylamino-ethyl ester isobutene dimethyl sulfate, cetyl trimethyl ammonium bromide, the  chemical compound, quaternary ammonium compound, benzyl two (2-chloroethyl) ethyl ammonium bromide, the cocos nucifera oil trimethyl ammonium chloride, the cocos nucifera oil trimethylammonium bromide, cocos nucifera oil methyl dihydroxy ethyl ammonium chloride, cocos nucifera oil methyl dihydroxy ethyl ammonium bromide, the decyl triethyl ammonium chloride, the decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl ethoxy chlorination ammonium bromide, C 12-15Dimethyl hydroxyethyl ammonium chloride, C 12-15Dimethyl ethoxy chlorination ammonium bromide, coco dimethyl hydroxyethyl ammonium chloride, coco dimethyl ethoxy ammonium bromide, myristyl trimethyl ammonium methyl sulfate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (oxyethylene group) 4 ammonium chloride, lauryl dimethyl (oxyethylene group) 4Ammonium bromide, N-alkyl (C 12-18) dimethyl benzyl ammonium chloride, N-alkyl (C 14-18) dimethyl benzyl ammonium chloride, N-myristyl dimethyl benzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C 12-14) dimethyl 1-naphthyl methyl ammonium chloride, trimethyl-ammonium halide, alkyl trimethyl ammonium salt, dialkyl dimethyl ammonium salt, lauryl trimethyl ammonium chloride, ethoxylation alkyl amido alkyl dialkyl ammonium salt, ethoxylation trialkyl ammonium salts, dialkyl benzene dialkylammonium chloride, N-DDAC, N-myristyl dimethyl benzyl ammonium chloride monohydrate, N-alkyl (C 12-14) dimethyl 1-naphthyl methyl ammonium chloride, dodecyl dimethyl benzyl ammonium chloride, dialkyl benzene alkyl ammomium chloride, lauryl trimethyl ammonium chloride, alkyl benzyl ammonio methacrylate, alkyl benzyl dimethyl ammonium bromide, C 12Trimethylammonium bromide, C 15Trimethylammonium bromide, C 17Trimethylammonium bromide, dodecylbenzyl triethyl ammonium chloride, diallyl dimethyl ammoniumchloride (DADMAC), alkyl dimethyl ammonium chloride, alkyl dimethyl ammonium halide, three (cetyl) ammonio methacrylate, decyl trimethylammonium bromide, dodecyl triethyl group ammonium bromide, Tetradecyl Trimethyl Ammonium Bromide, methyl trioctylphosphine ammonium chloride, POLYQUAT 10 TM, tetrabutyl ammonium bromide, benzyltrimethylammonium bromide, cholinester, benzalkonium chloride, department draw halide salts, the MIRAPOL of oronain chemical compound, cetyl pyridinium bromide , hexadecylpyridinium chloride , quaternised polyoxy ethyl alkylamine TM, ALKAQUAT TM, alkyl pyridine  salt; Amine, amine salt, amine oxide, acid imide pyrroles  (imide azolinium) salt, protonated season type acrylamide, methylated season type polymer and cationic guar gum.
12. each compositions among the claim 1-11, it comprises the polyvidone polymer as surface stabilizer, and the molecular weight of this polymer is about 40000 dalton or still less.
13. each compositions among the claim 1-12 also comprises one or more non-tacrolimuss or non-sirolimus activating agent.
14. each compositions among the claim 1-13, wherein said composition is dispersed in the biological associated media again, makes the particulate effective particle mean size of tacrolimus be selected from following: less than about 2 microns, less than about 1900nm, less than about 1800nm, less than about 1700nm, less than about 1600nm, less than about 1500nm, less than about 1400nm, less than about 1300nm, less than about 1200nm, less than about 1100nm, less than about 1000nm, less than about 900nm, less than about 800nm, less than about 700nm, less than about 650nm, less than about 600nm, less than about 550nm, less than about 500nm, less than about 450nm, less than about 400nm, less than about 350nm, less than about 300nm, less than about 250nm, less than about 200nm, less than about 150nm, less than about 100nm, less than about 75nm with less than about 50nm.
15. the compositions of claim 14, wherein biological associated media are selected from aqueous solution, the aqueous acid of water, electrolyte aqueous solution, salt, aqueous solution and its combination of alkali.
16. each compositions is wherein used with same dose among the claim 1-15, when the blood plasma of the mammalian subject after using is analyzed, and the T of described tacrolimus MaxT less than non-nano granule tacrolimus Max
17. the compositions of claim 16, wherein:
(a) use described T with same dose MaxBe selected from and be not more than the shown T of non-nano granule tacrolimus formulations MaxAbout 90%, about 80%, about 70%, about 60%, about 50%, about 30%, about 25%, about 20%, about 15%, about 10% and about 5%;
(b) after being applied to fasted subjects, said composition demonstrates and is selected from following T Max: less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour with less than about 30 minutes; Perhaps
(c) combination (a) and (b).
18. each compositions is wherein used with same dose among the claim 1-17, when the blood plasma of the mammalian subject after using is analyzed, and the C of described tacrolimus MaxC greater than non-nano granule tacrolimus formulations Max
19. the compositions of claim 18 is wherein used with same dose, described C MaxBe selected from: greater than the shown C of non-nano granule tacrolimus formulations MaxAt least about 50%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%, at least about 1100%, at least about 1200%, at least about 1300%, at least about 1400%, at least about 1500%, at least about 1600%, at least about 1700%, at least about 1800% or at least about 1900%.
20. each compositions is wherein used with same dose among the claim 1-19, when the blood plasma of the mammalian subject after using was analyzed, the AUC of described tacrolimus was greater than the AUC of non-nano granule tacrolimus formulations.
21. the compositions of claim 20, wherein use with same dose, described AUC is selected from: greater than the shown AUC of the non-nano granular preparation of described immunosuppressant at least about 25%, at least about 50%, at least about 75%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, at least about 750%, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, at least about 1000%, at least about 1050%, at least about 1100%, at least about 1150% or at least about 1200%.
22. each compositions among the claim 1-21 when using under the condition on the feed, and is compared under fasted conditions, it does not have to produce significantly different absorption level.
23. the compositions of claim 22, wherein with respect to fasting state, when using under the state on the feed, the absorption difference of tacrolimus compositions is selected from: less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5% with less than about 3%.
24. each compositions among the claim 1-23 is wherein used the said composition bioequivalence under the state experimenter being used said composition on the feed to the people under fasting state.
25. each compositions is used to make the purposes of medicine among the claim 1-24.
26. the purposes of claim 25, wherein said medicine can be used for organ rejection's the prophylactic treatment or the treatment of psoriasis or other immune diseases.
27. the purposes of claim 25, wherein this medicine is injectable pharmaceutical composition, and this injectable pharmaceutical composition forms subcutaneous or intramuscular storage point, so that long-term release.
28. make injectable Nanoparticulate tacrolimus method for compositions for one kind, this method comprises makes the tacrolimus granule contact a period of time under certain condition with at least a surface stabilizer, and described condition and time are enough to provide the tacrolimus granule of effective particle mean size less than about 2000nm.
29. the method for claim 28, wherein said contact comprise grinding, wet grinding, homogenize, precipitation or supercritical fluid particle generation technique.
30. the method for claim 28, also comprise and in the Nanoparticulate tacrolimus compositions, add nano-particle sirolimus compositions, wherein nano-particle sirolimus compositions comprises sirolimus granule and the surface stabilizer of effective particle mean size less than about 2000nm, and wherein the sirolimus surface stabilizer can be identical or different with the tacrolimus surface stabilizer.
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